Method of treating rhinitis with C-type natriuretic peptides

ABSTRACT

The problem to be solved by the present invention is to provide an effective and safe therapeutic preparation for rhinitis, which not only has significant effects on improvement in rhinitis, in particular allergic rhinitis, but also is rapid in manifestation of efficacy, fast-acting, and long-lasting, without local side effects. 
     Means for solving the problem is a therapeutic preparation for rhinitis, in particular allergic rhinitis, comprising C-type natriuretic peptide (CNP) or B-type natriuretic peptide (BNP) as the active ingredient.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.15/160,268, filed May 20, 2016, which is a continuation of U.S.application Ser. No. 14/193,017, filed Feb. 28, 2014 and now U.S. Pat.No. 9,358,270, which is a continuation of U.S. application Ser. No.13/392,657, filed Nov. 6, 2012, which is a national stage filing under35 U.S.C. § 371 of international application PCT/JP2010/064644, filedAug. 27, 2010, the entire disclosures of which are incorporated hereinby reference.

TECHNICAL FIELD

The present invention relates to a therapeutic preparation for rhinitiscomprising C-type natriuretic peptide (CNP) or B-type natriureticpeptide (BNP) as the active ingredient.

BACKGROUND ART

1. Rhinitis

Rhinitis refers to what is known as an inflammation of the so-callednasal mucous membrane, and histopathologically it is an exudativeinflammation, often exhibited as pyogenic inflammation and allergicinflammation. In any cases, it is characterized by exudation of fluidcomponents from the blood vessels, edema, cellular exudates andsupersecretion.

Rhinitis includes various types such as acute rhinitis (so-called coldin the nose), chronic rhinitis, and allergic rhinitis depending on thecause and symptoms; usually, it is classified into four types dependingon their causes and symptoms, namely infectious rhinitis, hypersensitivenon-infectious rhinitis, irritant rhinitis, and others, as shown below.

TABLE 1 1. Infectious (a) Acute rhinitis (b) Chronic rhinitis 2. Hyper-(a) Combined type (i) Allergic Perennial allergic sensitive(hypersensitive rhinitis non-infectious nose) Seasonal allergic rhinitis(ii) Vasomotor rhinitis Non-allergic (idiopathic rhinitis) Non-allergicrhinitis with eosinophilia syndrome (b) Rhinorrhea type Gustatoryrhinitis Cold air inhalation-induced rhinitis Senile rhinitis (c)Congestive type Drug-induced rhinitis Psychogenic rhinitis Pregnancyrhinitis Endocrine rhinitis Cold-induced rhinitis (d) Dry type 3.Irritant (a) Physical irritant-induced rhinitis (b) Chemicalirritant-induced rhinitis (c) Radiation-induced rhinitis 4. Others (a)Atrophic rhinitis (b) Specific granulomatous rhinitis

Hereinafter, rhinitis of these types is explained.

Infectious rhinitis is classified into acute rhinitis (the so-calledcold in the nose) which progresses within a short period, and chronicrhinitis which persists for along period. Infective chronic paranasalsinusitis, in which nasal cavities mainly around the ethmoid sinus andmiddle nasal meatus are affected, is also included in the infectiousrhinitis.

Of the infectious rhinitis, most cases of the acute rhinitis areclassified as a cold in the nose induced by infections mainly viral, butthere are also many cases of acute simple rhinitis.

Symptoms of acute viral rhinitis (the cold) are characterized by runnynose, stuffy nose, and postnasal rhinorrhea in which nasal drip flowsinto the throat, coughing, slight fever and others. To relieve stuffynose, vasoconstrictive agents such as spray-type nasal drop preparationsof phenylephrine and oral medicines of pseudoephedrin are used. However,the use of such spray preparations must be limited to 3 to 4 days. Whenused for a longer period than this, the effectiveness of the medicine isreduced and a rebound phenomenon, in which the nasal mucous membranesbecome more congested than prior to the use, occurs. In addition, whileantihistamine drugs have an effect to suppress runny nose, they alsohave side effects such as drowsiness.

In contrast, contributing factors of acute simple rhinitis includesinusitis, tonsillitis, and inflammation of adjacent organs such as theadenoids, as well as dust, soot, tobacco, air pollution, extremetemperature change, excessive dryness and moistness. Symptoms initiatewith sneezing, and include excess rhinorrhea (nasal drip), nasalocclusion (stuffy nose), and impairment of the sense of smell; theyresemble the symptoms of a cold of the nose, but do not include systemicsymptoms such as fever. The nasal mucous membrane congests and swells.Disease is usually cured within 10 days, but occasionally bacterialinfection occurs, worsening the symptoms and causing a fever. Aprolonged course of the disease results in sinusitis or chronicrhinitis. For treatment, patients are rested and kept warm, andsupportive measures are also taken, such as the use of antifebriles,analgesics, antitussive agents, and anti-inflammatory agents; when abacterial infection occurs, antibiotics are used.

Chronic rhinitis is a long-term infectious rhinitis; when contributingfactors of acute rhinitis are not improved, acute rhinitis turns intochronic rhinitis. Chronic rhinitis is often associated with chronicsinusitis. Chronic rhinitis has three pathological conditions, eachreferred to as chronic simple rhinitis, chronic hypertrophic rhinitis,and atrophic rhinitis.

Chronic simple rhinitis is a pathological condition in which the mucousmembrane of the nasal cavities swells chronically due to repeated acuterhinitis. Symptoms of chronic simple rhinitis are mostly identical tothose of hypertrophic rhinitis, and include nasal occlusion, excessrhinorrhea, impairment of the sense of smell and headache. However, itdiffers from chronic hypertrophic rhinitis in that swelling of the nasalmucous membrane is improved by vasoconstrictive agents. For treatment,removal of contributing factors is most important; conservativemanagement such as the application of drugs and use of anti-inflammatoryagents is also carried out.

Chronic hypertrophic rhinitis is caused by severe long-lastinginflammation. Chronic hypertrophic rhinitis is the most prevalentpathological condition among the chronic rhinitides, and exhibits severeswelling and thickening of the nasal mucous membrane.

Chronic atrophic rhinitis refers to a pathological condition wherein themucous membrane of the nasal cavities and the bone tissues of the nosebecome atrophied, resulting in widened nasal cavities. Stuffy noseoccurs on both sides and purulent nose drips are discharged. Dischargesinside the nose attach to the wall of the nasal cavity in a crust likemanner, releasing a bad odor.

Hypersensitive non-infectious rhinitis is a rhinitis whereininflammation is caused by the mucous membrane of the nasal cavities thathave become hypersensitive due to diathesis and some other reasons, sothat it occurs by stimulations other than viruses and bacterialinfection.

Furthermore, hypersensitive non-infectious rhinitis can be classifiedinto combined-type rhinitis (hypersensitive nose), rhinorrhea-typerhinitis, congestive-type rhinitis, and dry-type rhinitis. In addition,combined-type rhinitis (hypersensitive nose) is further classified intoallergic rhinitis and non-allergic rhinitis. Furthermore, allergicrhinitis can be classified into, from their favored onset timing,perennial allergic rhinitis and seasonal allergic rhinitis, andnon-allergic rhinitis can be classified into vasomotor rhinitis(idiopathic rhinitis) and non-allergic rhinitis with eosinophiliasyndrome. In addition, rhinorrhea-type rhinitis can be classified intogustatory rhinitis, cold air inhalation-induced rhinitis, and senilerhinitis; and congestive-type rhinitis can be classified intodrug-induced rhinitis, psychogenic rhinitis, pregnancy rhinitis, andcold-induced rhinitis.

Combined-type rhinitis (hypersensitive nose) usually accompanies some ofthe symptoms including sneezing, watery rhinorrhea, and nasal occlusion(stuffy nose); for example, sneezing with watery rhinorrhea, sneezingwith watery rhinorrhea and nasal occlusion.

Of the combined-type rhinitides (hypersensitive nose), allergic rhinitisis induced by the immune response of the body against causativesubstances in the external environment. Causative substances of allergicrhinitis generally include house dust, house dust mites, fungi, pollens,grasses, trees, and animals. More specifically, allergic rhinitis is atype-I allergic disease of the nasal mucous membrane, and ischaracterized by, in principle, paroxysmal repetitive sneezing, wateryrhinorrhea, and nasal occlusion. Since allergic rhinitis is a type-Iallergic disease, patients often have an allergic disposition (pasthistory, complication, and family history of allergy), and arecharacterized by an increased serum level of specific IgE antibodies,increases in the local mast cells as well as local and bloodeosinophils, and enhancement of non-specific sensitivity of the mucousmembrane.

Of the allergic rhinitides, perennial allergic rhinitis is mostly causedby house dust and house dust mites, and seasonal allergic rhinitis ismostly caused by pollen.

Of the non-allergic rhinitides, vasomotor rhinitis (idiopathic rhinitis)is a kind of chronic rhinitis with some symptoms similar to those ofgeneral allergic rhinitis, i.e., nasal occlusion (stuffy nose),sneezing, and watery rhinorrhea (runny nose), but showing no apparentantigens. Symptoms include, in addition to stuffy nose, swelling of themucous membrane with various colors from red to violet. Sometimes mildinflammation is observed in the paranasal sinuses. For treatment,anti-histamine drugs and anti-allergy agents are used.

Of the non-allergic rhinitides, non-allergic rhinitis with eosinophiliasyndrome refers to a disease wherein an allergy test result is negative,but the amount of eosinophils in the nasal drip alone increases to someextent.

The rhinorrhea-type hypersensitive non-infectious rhinitis ischaracterized by rhinorrhea, and there are three types: gustatoryrhinitis, cold air inhalation-induced rhinitis, and senile rhinitis.Gustatory rhinitis often occurs during eating highly-irritating foods orvery hot foods. Cold air inhalation-induced rhinitis is a rhinorrheainduced by inhalation of cold air, which is famous as the skier's nose.Senile rhinitis is also characterized by watery rhinorrhea, but itscause is unknown.

Of the hypersensitive non-infectious rhinitides, congestive rhinitis ischaracterized by nasal occlusion as a predominant symptom, and isfurther classified into drug-induced rhinitis, psychogenic rhinitis,pregnancy rhinitis, endocrine rhinitis, and cold-induced rhinitis. Anyof these types of rhinitis is characterized by congestion of the mucousmembrane, and a stuffy nose is often observed.

Among them, drug-induced rhinitis is characterized by stuffy nose as apredominant symptom, which is reportedly possibly induced as a sideeffect of long-term continuous administration of drugs such assympatholytic antihypertensive drugs, vasodilatory antihypertensivedrugs, -stimulation antihypertensive drugs, bronchodilators,anti-depressants, and contraceptive pills. However, the most frequentlyobserved cause is the abuse of a vasoconstrictor nasal drop preparationagainst nasal occlusion. Psychogenic rhinitis is observed with chronicstress, depression, and neurosis, and is characterized by nasalocclusion. Pregnancy rhinitis occurs in the second trimester or later ofpregnancy, and its onset is considered to be particularly associatedwith actions of female hormone, especially estrogen, on the bloodvessels of nasal mucous membranes and on autonomic receptors. Endocrinerhinitis is known with emphasis on a decrease in thyroid activity. Butthe number of the case is small. Cold-induced rhinitis is considered tobe induced by reflex vasodilation in nasal mucosa, via cold stimulationof the body, in particular the hands and feet.

Of the hypersensitive non-infectious rhinitides, dry-type rhinitis (drynose) is presumed to be induced as follows: when the humidity in a roombecomes 20% or lower due to dry air and heating in winter, symptoms suchas dry mucous membrane, crusting, and nasal bleeding occur, andhypersensitivity to irritation increases due to drying of the mucouslayer, leading to nasal dryness and nasal occlusion sensations.

Irritant rhinitis is often caused by the working environment of anoccupation, and is classified into physical irritant-induced rhinitis,chemical irritant-induced rhinitis and radiation-induced rhinitis basedon the cause. Such physical irritant-induced rhinitis and chemicalirritant-induced rhinitis develop by physical or chemical, acute orchronic irritation of mucous membranes. Inflammation is sometimes causedby radiation of nasal mucous membranes, which is calledradiation-induced rhinitis.

Other types of rhinitis include atrophic rhinitis and specificgranulomatous rhinitis. As symptoms of atrophic rhinitis (ozena), thenasal mucous membrane becomes thin and hard, and the nasal cavitiesextend to induce dryness; however, this type of rhinitis is currentlyrare in Japan. Specific granulomatous rhinitis is a rhinitis associatedwith granuloma, and includes specific rhinitis (tuberculosis, syphilis,etc.), sarcoidosis, and Wegener granulomatosis; however, the number ofcases is extremely small.

In any case, rhinitis is a state of the nasal mucous membrane that isswelling by inflammation, characterized by symptoms such as runny noseand stuffy nose, which disturbs the daily lives of patients whoexperience difficulty in breathing; thus, rhinitis is a troublesomedisease.

2. Treatment of Rhinitis

In the treatment of rhinitis, in particular allergic rhinitis, methodsare generally selected based on the combination of severity level anddisease type. The selection is not standardized, but according to“Guidelines for medical care of nasal allergies, 2009 edition” (editedby the committee for creation of guidelines for medical care of nasalallergies) treatment methods are as follows.

For mild cases, the first choice should be second-generationantihistamine drugs or chemical mediator releasing suppressants. Whenside effects such as drowsiness and dry mouth are not observed,first-generation antihistamine drugs having a fast-acting property maybe administered.

In moderate cases, for sneezing/rhinorrhea type, one of the following:

(1) second-generation antihistamine drugs,

(2) chemical mediator releasing suppressants, or

(3) steroid nasal sprays,

is selected, and if necessary, either (1) or (2) is combined with (3).

In moderate cases, for nasal-occlusion type or mixed type withparticularly severe nasal-occlusion cases, one of the following:

(1) anti-leukotriene drugs,

(2) anti-prostaglandin D2/thromboxane A2 drugs, or

(3) steroid nasal sprays,

is selected, and if necessary, either (1) or (2) is combined with (3).

In severe cases, when sneezing and rhinorrhea are particularly severe, asecond-generation antihistamine drug is combined with a steroid nasalspray. Meanwhile, among severe cases of nasal-occlusion type or mixedtype wherein nasal occlusion is particularly severe, an anti-leukotrienedrug or anti-prostaglandin D2/thromboxane A2 drug is combined with asteroid nasal spray.

Attempts to remove and avoid antigens are required in any case; whensequential therapy is possible, application of specific immunotherapy isa choice, with which long-term remission can be expected. In cases ofapparent morphological defects such as deviation of the nasal septum, orin cases wherein effects of drug therapy on nasal occlusion areinsufficient, operative therapy is one choice of treatment.Effectiveness of antihistamine nasal sprays has been reported, but theyare considered to be inferior to steroid nasal sprays.

As described above, representative treatments of allergic rhinitisinclude removal and a voidance of allergens, drug therapy, specificimmunotherapy, and operative therapy; drugs used in the drug therapy canbe classified into the following drug groups based on their actionmechanism: steroids, histamine receptor antagonists, chemical mediatorreleasing suppressants, thromboxane A2 receptor antagonists, thromboxaneA2 synthesis inhibitors, leukotriene antagonists, and Th2 cytokineinhibitors.

Among them, examples of steroids include beclomethasone (brand name:Beconase, Aldecin, Rhinocort, Salcoat), fluticasone (brand name:Flixonase), etc. Examples of histamine receptor antagonists includeketotifen (brand name: Zaditen), mequitazine (brand name: Zesulan),fexofenadine (brand name: Allegra), ebastine (brandname: Ebastel),bepotastine (brandname: Talion), olopatadine (brand name: Allelock),loratadine (brand name: Claritin), etc. Examples of chemical mediatorreleasing suppressants include cromolyn (brand name: Intal) andtranilast (brand name: Rizaben), etc. Examples of thromboxane A2receptor antagonists include seratrodast (brand name: Bronica) andramatroban (band name: Bynas), etc. Examples of thromboxane A2 synthesisinhibitors include ozagrel (brand name: Domenan or brand name: Vega),etc. Examples of leukotriene antagonists include montelukast (brandname:Singulair, Kipres) and pranlukast (brand name: Onon), etc. Examples ofTh2 cytokine inhibitors include suplatast (brand name: IPD), etc.

Thus, while there are a number of drugs usable as therapeuticpreparations for allergic rhinitis, steroids or histamine receptorantagonists are frequently used for moderate cases, and a combination ofsteroids and histamine receptor antagonists is used for severe cases.

Meanwhile, steroid nasal sprays elicit some local side effects such asnasal irritation, dryness, burning sensation of the nose, and nasalbleeding. In addition, when steroids are used for a long time, cautionshould be taken to avoid steroid withdrawal difficulty, andcomplications of infection should be a concern. There are a considerablenumber of cases of rhinitis that show resistance to steroid therapy.Furthermore, steroid nasal sprays do not have a long duration ofeffectiveness, and in the case of adult patients, application of about 4times a day is necessary. Accordingly, many patients hesitate to usesteroid nasal sprays, and there is a report stating that more than halfof the patients did not take drugs in accordance with theirprescription.

Furthermore, while antihistamine drugs suppress allergic reactions andtheir symptoms, they have disadvantages that they cause dryness in thenasal mucous membrane and drowsiness. In addition, while injection ofallergens (hyposensitization therapy) leads to a long-term immunologicaltolerance against a specific causative substance, it takes from severalmonths to several years for the manifestation of sufficient effects.

Under such circumstances, development of a novel therapeutic preparationfor rhinitis that is not only efficacious and safe for patients withrhinitis, in particular patients with allergic rhinitis, but also hasfewer local side effects without complication of infections, has beenawaited. Moreover, development of a therapeutic preparation for rhinitisthat is also efficacious for patients with severe cases who showtreatment resistance to steroids has been awaited.

3. Natriuretic Peptides:

There are three known families of natriuretic peptides (NPs), namedatrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), andC-type natriuretic peptide (CNP); their well-known members are composedof 28, 32, and 22 amino acid residues, respectively.

(1) ANP and BNP:

ANP and BNP are synthesized mainly by the atria and the ventricles,respectively, and released from the heart into the whole body. It isthought that nearly 100% of the circulating ANP and BNP in the bloodoriginate from the heart. These ANP and BNP are reported to be deeplyinvolved in a numerous diseases, including hypertension, cardiomegaly,cardiac failure, myocardial infarction, valvular heart disease, cardiacdysrhythmia, and pulmonary hypertension.

Human ANP is a peptide produced and released by atrial cardiocytes, andis composed of 28 amino acids, of which the 7^(th) cysteine and the23^(rd) cysteine are bonded by a disulfide bond to form a ringstructure. ANP has been shown to have diuretic effects in the kidneysand relaxes/dilates vascular smooth muscle cells in the blood vessels.In contrast, human BNP is a peptide produced and released by ventricularcells, and is composed of 32 amino acids, of which the 10^(th) cysteineand the 26^(th) cysteine are bonded by a disulfide bond to form a ringstructure. BNP also possesses both diuretic and vasodilating effects.BNP was originally isolated and identified in the porcine brain in Japanin 1988, and is also called brain natriuretic peptide.

Both ANP and BNP bind to the receptor NPR-A (also called GC-A) having aguanylate cyclase domain, and exert their effects as stated above bystimulating the production of cGMP. In fact, secretion of ANP isstimulated in response to an increase in the atrial pressure by itsdistension in congestive heart failure, etc., and through its action asstated above, ANP relieves the symptoms of congestive heart failure,etc. Likewise, BNP's release is stimulated during certain conditionsincluding myocardial infarction, and BNP, through its action asdescribed above, relieves the symptoms associated with myocardialinfarction, etc. (Refer to non-patent literature 1). Although most ofthe circulating BNP derives from the ventricles, some BNP is released bythe atria. In cardiac failure, the level of expression of both ANP andBNP increases to as much as 100 times more the normal level, but theincrease of BNP expression is reported to be both greater and fasterthan that of ANP. While ANP (hANP) is marketed as a prescription drugfor treating acute cardiac failure in Japan, BNP is clinically used inthe United States.

(2) CNP:

CNP, which was once thought to function only as a brain peptide becauseit was first found in the brain, has now been clarified to exist in theperiphery as well. In the vascular walls, in particular, CNP specificreceptors were found to be abundant in the smooth muscle cells, and CNPto be produced by the cells of the monocyte/macrophage linage and theendothelial cells. For those reasons, CNP is speculated to function inthe vascular walls as a local mediator involved in inhibition of growthof vascular smooth muscle cells. Its clinical application is currentlybeing investigated for possible prevention of restenosis by CNPadministration, which occurs with a certain frequency after percutaneoustransluminal coronary angioplasty (PTCA) performed on patients withischemic heart failure.

Recently it has been reported that intravenous administration of CNPremarkably improves cardiomegaly and fibrosis associated with myocardialinfarction, and improves cardiac functions in animal experiments.Cardiac fibrosis is known to cause diastolic ventricular failure andcardiac dysrhythmia. Since CNP possesses a powerful action to suppressfibroblast proliferation, the potential of CNP as an anti-fibroticmedication for the heart is under investigation. Since CNP is a hormoneoccurring naturally in the body, there is little concern of adverse sideeffects; accordingly clinical application of CNP as a therapeuticpreparation for arteriosclerotic diseases and heart diseases isexpected. Here, examples of CNP include CNP-22 composed of 22 aminoacids, and CNP-53 wherein 31 amino acid residues are attached to theN-terminal of CNP-22.

(3) Natriuretic Peptide Receptors:

Natriuretic peptide receptors are classified into three subtypes; NPR-Areceptor (also called GC-A) and NPR-B receptor (also called GC-B) bothof which contain a guanylate cyclase domain, and NPR-C receptor whichlacks a guanylate cyclase domain. It is known that ANP can bind to NPR-Aand NPR-C receptors, BNP can bind to NPR-A and NPR-C receptors, and CNPcan bind to NPR-B and NPR-C receptors.

The activation of NPR-A receptors is suggested to induce vasodilation, adiuretic effect, and inhibition of cell growth, while NPR-B receptorsare abundant in vascular smooth muscle cells and thought to be involvedin the growth inhibition of vascular smooth muscle cells.

(4) Relationship Between Natriuretic Peptides and the Immune System:

Historically, natriuretic peptides were first discovered as a peptidereleased from the atria, later named ANP, and its vasodilating anddiuretic actions gathered attention. BNP and CNP were then discovered aspeptides similar to ANP. This historical background offers anexplanation as to why any attention to the relationship betweennatriuretic peptides and the immune system have been focused on thoserelated to the cardiovascular system. CNP knock-out mice demonstratedimpaired growth of cartilage resulting in a dwarfism-like phenotype(refer to Non-patent literature 2), which directed some interest to therelationship between arthritis and natriuretic peptides.

ANP is implicated in playing a role in arthritis and sepsis as itinhibits the release of inflammatory cytokines including tumor necrosisfactor (TNF-α) and interleukin 1β (IL-1β) by macrophages (refer toNon-patent literature 3). This literature, however, does not mentionANP's relationship with rhinitis.

Similarly, the blood concentration of BNP has been reported to increasewith the rejection response following heart transplant, and therefore itis suggested that it is associated with immune regulation in thecardiovascular system (refer to Non-patent literature 4). However, thisliterature does not describe any connection between BNP and rhinitis.

Taking into account the observation that there is an increase in theblood concentration of BNP during the heart graft rejection, Kuroski deBold et al. have investigated the immunoregulatory action of natriureticpeptides, and have demonstrated that both ANP and BNP inhibit thelymphocyte growth (refer to Non-patent literature 5). However, there isno connection between natriuretic peptides and rhinitis mentioned inthis literature.

Chiurchiu et al. on the other hand have investigated theimmunoregulatory actions of BNP focusing on its association with heartdisease and sepsis, and showed that BNP promotes the release bymacrophages of pro-inflammatory cytokines such as arachidonic acid,prostaglandin E2 (PGE2), and leukotriene B4 (LTB4), and also promotesthe release of anti-inflammatory cytokines including interleukin 10(IL10). Thus, while BNP is indicated to have some action in theregulation of inflammatory responses, whether BNP acts overall tosuppress or promote inflammatory responses remains inconclusive in theliterature (refer to Non-patent literature 6). This literature also doesnot mention any connection between BNP and rhinitis.

Similarly, CNP is reported to be released by macrophages (refer toNon-patent literature 7), and while investigating the roles of CNP incardiac ischemia and myocardial damage after reperfusion, Scotland etal. report that CNP suppresses platelet aggregation and lymphocytemigration (refer to Non-patent literature 8). The connection between CNPand rhinitis, however, is not described in these literatures.

Likewise, Obata et al. examined the roles played by CNP in myocarditisusing a rat myocarditis model generated by injecting pig myosin. Theyreported that continuous administration of CNP for 1 week to the modelsuppressed necrosis and inflammation of the cardiac tissues, while atthe same time promoted the regeneration of blood vessels, therebypreventing functional loss of the heart (refer to Non-patent literature9). Nevertheless, there is no mention in this literature to suggest aconnection between CNP and rhinitis.

In addition, based on the observation that CNP knock-out mice show adwarfism-like phenotype, attention has been paid to the potentialconnection between CNP and cartilage growth. Agoston et al. demonstratedthat when incubated with Dexamethasone, the primary-culturedchondrocytes extracted from the tibial bones of mouse embryos hadsignificantly increased the expression of CNP genes (refer to Non-patentliterature 10). This literature, however does not describe anyconnections between CNP and rhinitis.

It is evident that the connections between natriuretic peptides and theimmune system have drawn increasing attention in recently years, but itis limited only to the inflammation of the cardiovascular system andarthritis, and the relationship between rhinitis and natriureticpeptides have never been reported.

(5) Reports on the Application of Natriuretic Peptides:

Following are some examples of a number of applications of CNP, BNP andANP.

Toshiko Koide and her colleagues have proposed a preparation forrepair/regeneration of tissues and organs, comprising a composition thatcomprises any of ANP, BNP, CNP, urodilatin (P-Uro), precursors thereof,derivatives thereof, or combinations thereof as an active ingredient,and that may comprise pharmaceutically commonly-used diluents,excipients, fillers, and auxiliary agents (refer to Patent Literature1).

However, specific examples of repair and regeneration of tissues andorgans relate only to the regeneration of myocardiocytes, hypodermaltissue, hair, and improvement of cracked, rough skin due to wet works;they all correspond to ANP administration. There is no statement thatimplies therapeutic preparations for treating rhinitis by means ofadministration of CNP or BNP.

Masaharu Tanaka and his colleagues have proposed a C-type natriureticpeptide exhibiting a growth inhibitory action of vascular smooth musclecells, as well as a growth inhibitory preparation of vascular smoothmuscle cells containing such peptide as its active ingredient (refer toPatent Literature 2).

This, however, relates to the use of CNP in a growth inhibitory agent ofvascular smooth muscle cells but does not imply application of CNP orBNP to therapeutic preparations for rhinitis.

Katsuhiko Nakada and his colleagues proposed an eye drop for promotinglacrimal secretion or for treating keratoconjunctival disorder,containing as its active ingredient a natriuretic peptide, and theylisted ANP, BNP and CNP as examples of usable natriuretic peptides(refer to Patent Literature 3).

This, however, only relates to the application of the property of ANP,CNP and BNP to promote lacrimal secretion in an eye drop for treatingkeratoconjunctival disorder, and does not indicate the use of CNP or BNPin a therapeutic preparation to treat rhinitis.

Kazuwa Nakao and his colleagues proposed a composition for increasingthe body height containing a guanyl cyclase B (GC-B) activator as theactive ingredient, which is to be administered to an individual withoutFGFR3 abnormality (refer to Patent Literature 4).

This indicates an application of CNP in a composition for increasing thebody height based on the finding that the nose-anus length in thetransgenic mice overexpressing CNP was larger than that in normallitters, but does not imply the use of CNP or BNP in a therapeuticpreparation for rhinitis.

Kazuwa Nakao and his colleagues also proposed a prophylactic agent ortherapeutic preparation for the inflammation of the joints containing aguanyl cyclase B (GC-B) activator such as CNP as an active ingredient(refer to Patent Literature 5).

However, this relates only to the application of CNP in a therapeuticpreparation or prophylactic preparation for inflammation of the jointsbased on the study revealing that, compared to their litter mates, thearticular cartilages grow thicker in the transgenic mice overexpressingCNP, along with the observation that the arthritis is repressed by thecontinuous administration of CNP to model animals of arthritis. Hencethis does not imply the application of CNP or BNP in a therapeuticpreparation for rhinitis.

In addition, Masaharu Tanaka and his colleagues reported that CNPdiffers from ANP and BNP in the structure, function and effects asstated below (refer to Patent Literature 2).

“At present, both ANP and BNP are thought to act as a hormone secretedby the heart into the blood, as well as a neurotransmitter, and to playan important role in maintaining the amount of body fluid andhomeostasis of blood pressure . . . . There are many unknown points inthe physiological role of CNP as a natriuretic peptide. Namely, sinceCNP has a primary amino acid sequence similar to that of ANP and BNP andshows a natriuretic action and a hypotensive action upon in vitroadministration, CNP was relegated to the natriuretic peptide family.However, because the natriuretic action and hypotensive action of CNPare significantly weaker than those of ANP and BNP (from 1/50 to 1/100),. . . CNP has held a unique position in the natriuretic peptide family,and has been presumed to be playing a role different from themaintenance of amounts of body fluid and homeostasis of blood pressure .. . . Comparing the structure of CNP with that of ANP/BNP, CNP differsfrom ANP or BNP in the following points . . . . Namely, the primaryamino acid sequence of CNP completely differs from that of ANP or BNP atthe exocyclic N-terminal domain; of the 17 amino acid residues in theendocyclic domain, 5 residues and 4 residues in CNP differ from those inANP and BNP, respectively. In addition, the structure of the exocyclicC-terminal domain of CNP largely differs from that of ANP or BNP, andCNP does not have a tail structure existing in ANP or BNP (in the caseof ANP and BNP, 5 amino acid residues and 6 amino acid resides,respectively, are attached to the C-terminal of the cyclic structure inANP and BNP; this structure is called a tail structure for descriptivepurposes). Thus-described structural differences between CNP and ANP/BNPare clearly involved in the manifestation of the above-mentionedcharacteristic pharmacological effects of CNP.”

REFERENCE LIST Patent Literature

-   Patent Literature 1: JP A 2008-162987-   Patent Literature 2: JP A 6-9688-   Patent Literature 3: JP A 2000-169387-   Patent Literature 4: WO 2005/094890-   Patent Literature 5: WO 2005/094889

Non-Patent Literature

-   Non-patent Literature 1: European J. Endocrinology, Vol. 135, p.    265, 1996.-   Non-patent Literature 2: Proceedings of the National Academy of    Sciences of the United States of America, Vol. 98, No. 7, p. 4016,    2001.-   Non-patent Literature 3: Annals of the Rheumatic Disease, Vol. 60,    Suppl. 3, iii, p. 68, 2001.-   Non-patent Literature 4: The Journal of Heart and Lung    Transplantation, Vol. 27, p. 31, 2008.-   Non-patent Literature 5: The Journal of Heart and Lung    Transplantation, Vol. 29, No. 3, p. 323, 2010.-   Non-patent Literature 6: Regulatory Peptides, Vol. 148, p. 26, 2008.-   Non-patent Literature 7: Experimental Hematology, Vol. 29, p. 609,    2001.-   Non-patent Literature 8: Proceedings of the National Academy of    Sciences, Vol. 102, No. 40, p. 14452, 2005.-   Non-patent Literature 9: Biochemical and Biophysical Research    Communications, Vol. 356, p. 60, 2007.-   Non-patent Literature 10: BMC Musculoskeletal Disorders, Vol. 7, p.    87, 2006.

SUMMARY OF INVENTION Problem to be Solved by Invention

Rhinitis, in particular allergic rhinitis, is a recurrent diseasetherefore its treatment requires continuous use of drugs. However, asmentioned above, while a steroid nasal spray has strong local effectseven in small amounts, occasionally it also induces local side effectssuch as nasal irritation, dryness, nose burning sensation, and nasalbleeding, and it inevitably involves complications of infection andothers due to long-term use. Antihistamine drugs suppress allergicreactions and their symptoms, but they have disadvantages such as dryingof the nasal mucous membrane and inducing drowsiness.

Accordingly, the object of the present invention is to provide a noveltherapeutic preparation for rhinitis that is not only efficacious andsafe for patients with rhinitis, in particular patients with allergicrhinitis, but also has no side effects such as nasal irritation,dryness, nose burning sensation, nasal bleeding, and drowsiness, etc.

Means of Solving the Problem

Considering these conditions, as a result of strenuous research efforts,the present inventor have found that C-type natriuretic peptide (CNP)and B-type natriuretic peptide (BNP), conventionally known as asuppressant of vascular smooth muscle cell proliferation, have excellentefficacy and safety as a therapeutic preparation for rhinitis, inparticular allergic rhinitis, and also confirmed that they can beapplied to patients with a sensitive mucous membrane without causingirritation symptoms; the present invention has thus been accomplished.

The present invention specifically includes the following.

[1] A therapeutic preparation for rhinitis comprising C-type natriureticpeptide (CNP) or B-type natriuretic peptide (BNP) as the activeingredient.

[2] The therapeutic preparation for rhinitis according to [1], whereinthe C-type natriuretic peptide (CNP) is CNP-22, CNP-53, or a CNPderivative in which any amino acid in the amino acid sequence of CNP-22or CNP-53 is deleted, substituted or added, and which has CNP activity.[3] The therapeutic preparation for rhinitis according to [1], whereinthe C-type natriuretic peptide (CNP) is CNP-22.[4] The therapeutic preparation for rhinitis according to [1], whereinthe B-type natriuretic peptide (BNP) is BNP-26, BNP-32, BNP-45, or a BNPderivative in which any amino acid in the amino acid sequence of BNP-26,BNP-32, or BNP-45 is deleted, substituted or added, and which has BNPactivity.[5] The therapeutic preparation for rhinitis according to [1], whereinthe B-type natriuretic peptide (BNP) is BNP-32.[6] The therapeutic preparation for rhinitis according to [1], whereinthe C-type natriuretic peptide (CNP) or B-type natriuretic peptide (BNP)is a chimeric peptide of CNP and BNP forming a ring structure by anintermolecular disulfide bond,in which the CNP is a peptide selected from the group consisting ofCNP-22, CNP-53, a peptide comprising any amino acid sequence of 5 ormore consecutive amino acids in the amino acid sequence of CNP-22 havingdeletion(s), substitution(s), or addition(s) of any 1-5 amino acid(s),or a peptide comprising any amino acid sequence of 5 or more consecutiveamino acids in the amino acid sequence of CNP-53 having deletion(s),substitution(s), or addition(s) of any 1-5 amino acid(s),and in which the BNP is a peptide selected from the group consisting ofBNP-26, BNP-32, BNP-45, a peptide comprising any amino acid sequence of5 or more consecutive amino acids in the amino acid sequence of BNP-26having deletion(s), substitution(s), or addition(s) of any 1-5 aminoacid(s), a peptide comprising any amino acid sequence of 5 or moreconsecutive amino acids in the amino acid sequence of BNP-32 havingdeletion(s), substitution(s), or addition(s) of any 1-5 amino acid(s),or a peptide comprising any amino acid sequence of 5 or more consecutiveamino acids in the amino acid sequence of BNP-45 having deletion(s),substitution(s), or addition(s) of any 1-5 amino acid(s), and whereinthe chimeric peptide has CNP activity or BNP activity; or a derivativeof the chimeric peptide.[7] The therapeutic preparation for rhinitis according to [1], whereinthe concentration of the C-type natriuretic peptide (CNP) or the B-typenatriuretic peptide (BNP) is 20-200 μg/g.[8] The therapeutic preparation for rhinitis according to [1], whereinthe concentration of the C-type natriuretic peptide (CNP) or the B-typenatriuretic peptide (BNP) is 50-200 μg/g.[9] The therapeutic preparation for rhinitis according to [1], whereinthe concentration of the C-type natriuretic peptide (CNP) or the B-typenatriuretic peptide (BNP) is 50-100 μg/g.[10] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is infectious rhinitis, hypersensitive non-infectiousrhinitis, irritant rhinitis, atrophic rhinitis, or specificgranulomatous rhinitis.[11] The therapeutic preparation for rhinitis according to [10], whereinthe infectious rhinitis is acute rhinitis or chronic rhinitis.[12] The therapeutic preparation for rhinitis according to [10], whereinthe hypersensitive non-infectious rhinitis is combined-type rhinitis(hypersensitive nose), rhinorrhea-type rhinitis, congestive-typerhinitis, or dry-type rhinitis.[13] The therapeutic preparation for rhinitis according to [12], whereinthe combined-type rhinitis (hypersensitive nose) is allergic rhinitis.[14] The therapeutic preparation for rhinitis according to [1], whereinthe allergic rhinitis is allergic rhinitis against at least one allergenselected from the group consisting of house dust, mite, cedar, orchardgrass, ragweed, and cat hair.[15] The therapeutic preparation for rhinitis according to [10], whereinthe irritant rhinitis is physical irritant-induced rhinitis, chemicalirritant-induced rhinitis or radiation-induced rhinitis.[16] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is atrophic rhinitis or specific granulomatous rhinitis.[17] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is mixed-type rhinitis, sneezing/rhinorrhea-type rhinitis,or nasal-occlusion-type rhinitis.[18] The therapeutic preparation for rhinitis according to [1], whereinthe dosage form is a nasal drop preparation selected from an ointmentpreparation, a gel preparation, a cream preparation, a lotionpreparation, a liquid preparation, a powder preparation or a spraypreparation.[19] The therapeutic preparation for rhinitis according to [1], whereinthe dosage form is a nasal drop preparation selected from a gelpreparation, a liquid preparation or a spray preparation.[20] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is rhinitis in a subject suffering from atopic dermatitis.[21] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is rhinitis with treatment resistance to steroids.[22] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is rhinitis in a subject having difficulty with withdrawalfrom steroids.[23] The therapeutic preparation for rhinitis according to [1], whereinthe rhinitis is rhinitis with treatment resistance to antihistaminedrugs.

Advantageous Effects of Invention

The therapeutic preparation for rhinitis of the present invention has,as is clear from the case studies mentioned below, not only excellentactions to improve rhinorrhea and nasal occlusion and to eliminatesneezing and nasal itching, but also superior permeability(absorbability) to the nasal mucous membrane and persistence. It isfast-acting and causes no irritation to patients with sensitive nasalmucous membranes, no local side effects as well as no systemic sideeffects such as induction of drowsiness.

The therapeutic preparation for rhinitis of the present invention hasCNP or BNP as the active ingredient, and its effects are more remarkablecompared to conventional steroids and antihistamine drugs. In terms ofpersistence of the effects, it is a revolutionary preparation that canrelieve symptoms by once-a-day administration.

Thus, without administration of steroids or antihistamine drugs, severesymptoms of rhinitis can be markedly improved by the use of thetherapeutic preparation for rhinitis of the present invention once aday, and even after discontinuation or stoppage of the use, worsening ofsymptoms need not be a concern.

Moreover, since the therapeutic preparation for rhinitis of the presentinvention has long-lasting drug efficacy, while at first, use twice aday in the morning and before bedtime is recommended, in many casesapplication once a day from day 2 and thereafter can significantlyimprove symptoms such as sneezing, rhinorrhea, and nasal occlusion.

Regarding the absorbability and fast-acting property, the effects aremanifested 10 to 20 min after the inhalation, and the preparation of thepresent invention is effective for any of mixed-type rhinitis,nasal-occlusion-type rhinitis, and sneezing/rhinorrhea-type rhinitis.Therapeutic effects in actual case studies (16 cases) showed that thepreparation of the present invention was effective in 100% of the cases.

Given that both BNP and ANP belong to the same family and share thecommon receptors, it was formerly assumed that BNP and ANP preparationspossess equivalent effects. When they were actually tested on patientswith rhinitis, allergic rhinitis in particular, however, BNPpreparations were revealed to have much greater pharmacological effectsthan ANP preparations. That is to say that BNP preparations arefaster-acting than ANP preparations, and lead to better improvements ofthe clinical symptoms and the effects lasted longer. On the other hand,ANP preparations unexpectedly resulted in much poorer improvements inthe rhinitis symptoms including runny nose, rhinorrhea and nasalocclusion, and in many cases, the symptoms showed no improvements orworsening. In cases where little improvement was evident with ANPpreparations, the improvement in the rhinitis symptoms was insufficientand only temporary. The finding that BNP as a therapeutic preparationfor rhinitis had more intense pharmacological effects than ANP belongingto the same family of natriuretic peptide was surprising.

The active ingredients of the present invention, CNP and BNP, arehormones which naturally occur in the body. Thus side effects are lessexpected and with adequate dosage, it is thought to have only a minoreffect on the hemodynamic status and hence it is safe to apply topatients with low or unstable blood pressure, allowing long-termadministration to chronic rhinitis patients. It shows a potency torhinitis greater than that of conventional steroids and antihistaminedrugs and it is also more rapid-acting, with an enhanced efficacy andleads to longer-lasting effects; in many cases, application of once aday from day 2 and thereafter can significantly improve symptoms such assneezing, rhinorrhea, and nasal occlusion. By the use of CNPpreparations or BNP preparations, in most cases, a mild to below mildand stable condition can be maintained without combined internal use ofantihistamine agents, and it is also advantageous that there are nolocal irritation symptoms that are observed with steroid sprays. Inaddition, the therapeutic preparation for rhinitis of the presentinvention has a merit of being efficacious to patients who are resistantto steroid therapy or patients of severe cases, which makes the presentinvention an unprecedented, important therapeutic preparation.

Thus, the therapeutic preparation for rhinitis of the present inventionis extremely effective in the treatment of various types of rhinitis, inparticular allergic rhinitis, and side effects need not be a concern;the present preparation can be applied to patients in whom conventionalsteroid nasal sprays and antihistamine drugs are not effective, orpatients in whom these drugs cannot be applied due to the possibility ofside effects, as well as young patients.

Therefore, practical application of the therapeutic preparation forrhinitis of the present invention as a therapeutic preparation forrhinitis replacing steroids and antihistamine drugs can be greatlyexpected.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram showing a comparison of the amino acid sequences ofhuman CNP peptide, human BNP peptide, and human ANP peptide. Each letterof the alphabet represents a type of amino acid expressed by one letter.There are three common regions in the amino acid sequence among thehuman CNP peptide, human BNP peptide and human ANP peptide, i.e., aminoacid sequences represented by “CFG”, “DRI” and “SGLGC” (SEQ ID NO:21);each peptide has four mutually different sequences divided by thesethree common sequences.

FIG. 2 is a graph showing the therapeutic effects on rhinitis before andafter spraying CNP nasal drop preparations. Each point represents eachcase. In all of nine (9) severe cases and one (1) moderate case,symptoms were improved to a mild degree by the 100 μg/ml CNP nasal droppreparation.

FIG. 3 is a graph showing the therapeutic effects on rhinitis before andafter spraying BNP nasal drop preparations. Each point represents eachcase. In two (2) most severe cases and one (1) moderate case, symptomswere improved to a mild degree by spraying the 50 μg/ml BNP nasal droppreparation. In addition, in one most severe case, symptoms wereimproved to a moderate degree by spraying the 50 μg/ml BNP nasal droppreparation. Similarly, in one (1) most severe case, symptoms wereimproved to a mild degree by spraying the 100 μg/ml BNP nasal droppreparation. Similarly, in one (1) severe case, symptoms were improvedto a mild degree by spraying the 200 μg/ml BNP nasal drop preparation.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

The present invention relates to a therapeutic preparation for rhinitiscomprising C-type natriuretic peptide (CNP) or B-type natriureticpeptide (BNP) as the active ingredient.

The CNP referred to herein means: CNP-22 composed of 22 amino acids, andCNP-53 in which 31 amino acid residues are attached to the N-terminal ofthe CNP-22, or derivatives thereof, without any particular limitationsprovided that they possess CNP activity. These CNP-22, CNP-53, and theirderivatives are all heretofore known, and can be made by chemicalsynthesis or genetic manipulations.

There are no particular limitations to the origin of CNP-22 and CNP-53,on the condition that they possess CNP activity, but the CNP derivedfrom mammals including human or birds are preferred, and morepreferably, the CNP derived from humans, monkeys, mice, rats or pigs,and particularly preferably, the CNP derived from humans.

The CNP derivatives means those having, in the amino acid sequences ofthe CNP-22 or CNP-53, a deletion(s), substitution(s) or addition(s) of1-5 amino acid(s), more preferably 1-3 amino acid(s), and furthermorepreferably 1 or 2 amino acid(s), while possessing CNP activity, oralternatively, those having a sequence with a homology of 85% or more,preferably 90% or more, and more preferably 95% or more with the aminoacid sequence of the CNP-22 or CNP-53, while possessing CNP activity.

Replaceable amino acids are substituted ideally by conservative aminoacid substitution. Conservative amino acids are classified by polaritiesand charge types. For example, nonpolar uncharged amino acids includeglycine, alanine, valine, leucine, isoleucine, proline, etc.; aromaticaminoacids include phenylalanine, tyrosine, tryptophan; polar unchargedamino acids include serine, threonine, cysteine, methionine, asparagine,glutamine, etc.; negatively-charged amino acids include asparaginicacid, glutamic acid; positively-charged amino acids include lysine,arginine, histidine. Thus, preferably amino-acid substitution is carriedout between conservative amino acids belonging to the same group. Here,when proline is to be replaced by another nonpolar uncharged amino acid,or when proline is to replace other nonpolar uncharged amino acids, itshould be noted that proline is not flexible in its spatial orientation.Similarly, when cysteine is to be replaced by another polar unchargedamino acid, or when cysteine is to replace other polar uncharged aminoacids, it should be noted that cysteine may form a disulfide bond withanother cysteine.

CNP derivatives may include those amidated or methoxylated at the Cterminal, CNP modified with addition of polyethylene glycol or fattyacids, and, glycosylated or alkylated CNP, provided they have CNPactivity.

Thus, any heretofore known CNPs with CNP activity can be used in thepresent invention. Examples may include CNP derivatives disclosed in JPA 6-9688, CNP derivatives disclosed in U.S. Pat. No. 5,583,108, andCD-NP disclosed in U.S. Pat. No. 6,818,619. It is possible to test thepresence/absence of CNP activity easily using heretofore knownprocedures, such as by testing a growth inhibitory action on thevascular smooth muscle cells, or by examining the activity of cGMPproduction in the cells expressing NPR-B receptors.

While any of CNP-22, CNP-53 and their derivatives can be used as theactive ingredient of the present invention, CNP-22 with a lowermolecular weight is more preferable in terms of absorbability. CNP-22can be manufactured by chemical synthesis or genetic manipulation usinghuman CNP genes, and is also available at, for example, PeptideInstitute Inc. as CNP-22 (human).

CNP that can be used in the present invention includes: purifiednaturally occurring CNP, genetically engineered CNP made using knowngenetic engineering procedures, CNP made using known chemical syntheticprocedures (such as solid-phase peptide synthesis by peptide syntheticmachinery). Basic methods including genetic engineering techniques,site-specific mutagenesis, and PCR, are commonly known or heretoforeknown, and are described in, for example, Current Protocols In MolecularBiology; John Wiley & Sons (1998), and JP A 5-207891.

The BNP of the present invention refers to: BNP-26 containing 26 aminoacids, BNP-32 containing 32 amino acids, BNP-45 containing 45 aminoacids, or their derivatives without any particular limitations providedthey possess BNP activity. BNP can also be high molecular weight Y-BNP(molecular weight of approximately 13000) which is formed by the removalof the signal peptide from a BNP precursor. BNP-32 and their derivativesare preferred. BNP-26, BNP-32, BNP-45, and their derivatives areheretofore known, and can be manufactured by chemical synthesis orgenetic manipulation.

There are no particular limitations to the origin of the BNP-26, BNP-32and BNP-45, provided they possess BNP activity, but the CNP derived frommammals including humans or birds is preferred, and the CNP derived fromhumans, monkeys, mice, rats or pigs is more preferred, and the CNPderived from humans is particularly preferred.

The BNP derivatives means, those having, in the amino acid sequences ofBNP-26, BNP-32 or BNP-45, a deletion(s), addition(s) or substitution(s)of 1-5 amino acid(s), more preferably 1-3 amino acid(s), and furthermorepreferably 1 or 2 amino acid(s), while possessing BNP activity, oralternatively, those having a sequence with a homology of 85% or more,preferably 90% or more, and more preferably 95% or more with the aminoacid sequence of BNP-26, BNP-32 or BNP-45, while possessing BNPactivity.

Replaceable amino acids in the BNP derivatives are similar to thereplaceable amino acids in the CNP derivatives.

BNP derivatives may include those amidated or methoxylated at the Cterminal of BNP, BNP modified with addition of polyethylene glycol orfatty acids, and, glycosylated or alkylated BNP, provided they have BNPactivity.

Thus, any heretofore known BNP with BNP activity can be used in thepresent invention. Examples may include BNP derivatives disclosed in JPA 2007-525213, BNP derivatives disclosed in U.S. Pat. No. 6,028,055, BNPderivatives disclosed in U.S. Pat. No. 5,114,923, and BD-NP disclosed inU.S. Pat. No. 6,818,619, or diuretic polypeptide or natriureticpolypeptide disclosed in JP A 2010-500032.

It is possible to easily test the presence/absence of BNP activity usingheretofore known procedures, such as an examination of the activity ofcGMP production in the cells expressing NPR-A receptors.

While any of BNP-26, BNP-32, BNP-45 and their derivatives can be used asthe active ingredient of the present invention, BNP-32 is preferable interms of drug efficacy and availability.

BNP of the present invention can be manufactured by chemical synthesisor genetic manipulation using human BNP genes (for example, refer to JPA5-207891, JP A2007-525957, JP A2007-525213), and BNP is alsocommercially available since it has already been launched.Alternatively, it is available from, for example, Peptide Institute Inc.as BNP-32 (human).

BNP that can be used in the present invention includes: purifiednaturally occurring BNP, genetically engineered BNP made using knowngenetic engineering procedures, BNP made using known chemical syntheticprocedures (such as solid-phase peptide synthesis by a peptidesynthesizer). Basic methods including genetic engineering techniques,site-specific mutagenesis, and PCR, are commonly known or heretoforeknown, and are described in, for example, Current Protocols in MolecularBiology; John Wiley & Sons (1998), and JP A 5-207891.

When the term “CNP or BNP” is used herein, it refers to either CNP orBNP, as well as the chimeric peptides of CNP and BNP. That is, as usedherein, the term “CNP or BNP” refers to CNP or BNP which may be: achimeric peptide of CNP and BNP forming a ring structure by anintermolecular disulfide bond, in which the CNP is a peptide selectedfrom the group consisting of CNP-22, CNP-53, a peptide comprising anyamino acid sequence of 5 or more consecutive amino acids in the aminoacid sequence of CNP-22 having deletion(s), substitution(s), oraddition(s) of any 1-5 amino acid(s), or a peptide comprising any aminoacid sequence of 5 or more consecutive amino acids in the amino acidsequence of CNP-53 having deletion(s), substitution(s), or addition(s)of any 1-5 amino acid(s),

and in which the BNP is a peptide selected from the group consisting ofBNP-26, BNP-32, BNP-45, a peptide comprising any amino acid sequence of5 or more consecutive amino acids in the amino acid sequence of BNP-26having deletion(s), substitution(s), or addition(s) of any 1-5 aminoacid(s), a peptide comprising any amino acid sequence of 5 or moreconsecutive amino acids in the amino acid sequence of BNP-32 havingdeletion(s), substitution(s), or addition(s) of any 1-5 amino acid (s),or a peptide comprising any amino acid sequence of 5 or more consecutiveamino acids in the amino acid sequence of BNP-45 having deletion(s),substitution(s), or addition(s) of any 1-5 amino acid(s), and whereinthe chimeric peptide has CNP activity or BNP activity; or a derivativeof the chimeric peptide.

Here, there are no particular limitations to the origin of CNP-22 andCNP-53, provided that they possess CNP activity, but the CNP derivedfrom mammals including humans or birds are preferred, and morepreferably, CNP derived from humans, monkeys, mice, rats or pigs, andmost preferably, CNP derived from humans. Similarly, there are noparticular limitations to the origin of BNP-26, BNP-32 and BNP-45,provided that they possess BNP activity, but the BNP derived frommammals including humans or birds is preferred, and the BNP derived fromhumans, monkeys, mice, rats or pigs is more preferred, and the BNPderived from humans is particularly preferred.

The derivatives of chimeric peptide of CNP and BNP mean those whichhave, in the amino acid sequences of the chimeric peptide of CNP andBNP, deletion(s), addition(s) or substitution(s) of preferably 1-5 aminoacid(s), more preferably 1-3 amino acid(s), and further more preferably1 or 2 amino acid(s), while possessing CNP or BNP activity.

Replaceable amino acids in the derivatives of the chimeric peptide ofCNP and BNP are similar to the replaceable amino acids in the CNPderivatives.

The derivatives of chimeric peptide of CNP and BNP may include thoseamidated or methoxylated at a C terminal of the chimeric peptide of CNPand BNP, those modified with the addition of polyethylene glycol orfatty acids in the chimeric peptide of CNP and BNP, and, glycosylated oralkylated chimeric peptide of CNP and BNP, provided that they have CNPor BNP activity.

Furthermore, the amino acid sequence of human CNP peptide represented bySEQ ID NO: 1 and the amino acid sequence of human BNP peptiderepresented by SEQ ID NO: 2 have, as shown in FIG. 1, four mutuallydifferent sequences divided by three common sequences represented by theamino acid sequences of “CFG”, “DRI” and “SGLGC” (SEQ ID NO:21).Accordingly, as a chimeric peptide of CNP and BNP, at least 14 kinds ofchimeric peptide represented by SEQ ID NOs 3-16 are listed based on thecombination of these four mutually different sequences. Then, thesechimeric peptides and their derivatives are considered to havecharacteristics common to CNP and BNP. Namely, these chimeric peptidesand their derivatives can be used as the active ingredient of thetherapeutic preparation for rhinitis of the present invention.

Thus, it is possible to use any heretofore known chimeric peptides ofCNP and BNP or derivatives thereof in the present invention, providedthat they possess CNP or BNP activity. For example, aquareticpolypeptides and natriuretic polypeptides disclosed as ABC-NP, ABC-NP1,BC-NP, etc. in JP A 2010-502231 may be used. These polypeptides areexemplified as amino acid sequence of SEQ ID Nos. 17-20.

The presence/absence of CNP or BNP activity can be easily tested usingheretofore known procedures, such as an examination of the activity ofcGMP production in the cells expressing NPR-A receptors or in the cellsexpressing NPR-B.

The chimeric peptides of CNP and BNP and their derivatives of thepresent invention can also be manufactured by chemical synthesis or bygenetic manipulation.

Indications of treatment by the therapeutic preparation for rhinitis ofthe present invention are not particularly limited, as long as thedisease is a so-called rhinitis, which induces an inflammation of thenasal mucous membrane and shows symptoms such as sneezing, runny noseand stuffy nose. The therapeutic preparation for rhinitis of the presentinvention may be applied to various types of rhinitis.

More specifically, rhinitides to which the therapeutic preparation forrhinitis of the present invention can be applied include infectiousrhinitis, hypersensitive non-infectious rhinitis, irritant rhinitis,atrophic rhinitis or specific granulomatous rhinitis; preferably it isinfectious rhinitis and hypersensitive non-infectious rhinitis in termsof therapeutic effects, and particularly preferably it is hypersensitivenon-infectious rhinitis.

Infectious rhinitis may be acute rhinitis or chronic rhinitis, andpreferably acute rhinitis. Using the therapeutic preparation forrhinitis of the invention, sneezing, excess rhinorrhea (nasal drip),nasal occlusion (stuffy nose), and impairment of the sense of smell,etc. can be rapidly cured.

Hypersensitive non-infectious rhinitis may be combined-type rhinitis(hypersensitive nose) including allergic rhinitis and non-allergicrhinitis; rhinorrhea-type rhinitis selected from gustatory rhinitis,cold air inhalation-induced rhinitis, and senile rhinitis;congestive-type rhinitis selected from drug-induced rhinitis,psychogenic rhinitis, pregnancy rhinitis, endocrine rhinitis andcold-induced rhinitis; or dry-type rhinitis.

Particularly preferred is allergic rhinitis or non-allergic rhinitis,and allergic rhinitis may include both perennial allergic rhinitis andseasonal allergic rhinitis. The therapeutic preparation for rhinitis ofthe invention exhibits extremely high efficacy and safety for allergicrhinitis, in particular perennial allergic rhinitis caused by house dustor mites, of which complete cure or long-term remission is considered tobe difficult, as its effective therapeutic preparation.

In addition, the present preparation is efficacious as a therapeuticpreparation for various types of rhinitis with symptoms such assneezing, runny nose and stuffy nose, derived from irritant rhinitissuch as physical irritant-induced rhinitis, chemical irritant-inducedrhinitis and radiation-induced rhinitis, as well as atrophic rhinitisand specific granulomatous rhinitis.

Furthermore, when indication of treatment by the present therapeuticpreparation for rhinitis is classified based on the symptoms, thepreparation can be effectively used for mixed-type rhinitis,nasal-occlusion-type rhinitis, or sneezing/rhinorrhea-type rhinitis inaccordance with “Guidelines for medical care of nasal allergies, 2009edition” (edited by the committee for creation of guidelines for medicalcare of nasal allergies).

Meanwhile, the meaning of the terms and the characteristics of thesymptoms of these various types of rhinitis are as descried above in theBackground Art.

The therapeutic preparation for rhinitis of the present invention isthose comprising C-type natriuretic peptide (CNP) or B-type natriureticpeptide (BNP) as the active ingredient, and its administration route anddosage form are not particularly limited.

Regarding the administration route, injections, oral medicines orexternal preparations can be used depending on the patient and symptoms.Specific examples include nasal drop preparations, gel preparations,ointment preparations, cream preparations, lotion preparations, spraypreparations, liquid preparations, nasal spray preparations, patchpreparations, aerosol preparations, jelly preparations, cataplasms,patch preparations, plaster preparations, suspension preparations,emulsion preparations, injection preparations, tablets, pills, capsules,granules, powders, etc.; liquid preparations may be adopted by selectingappropriate solvents. Any preparation can be produced in accordance withwell-known or heretofore known methods. Preferable examples includenasal drop preparations, liquid preparations, gel preparations, spraypreparations, ointment preparations, cream preparations, lotionpreparations, or powder preparations; more preferable examples are nasaldrop preparations, liquid preparations, gel preparations, powderpreparations, aerosol preparations or spray preparations, and aparticularly preferable example is liquid preparations.

Nasal drop preparations of the present invention may be a liquidpreparation or dry products such as a powder, and may comprise carriersor excipients, surfactants, suspending agents, mucosa-adherent bases andtonicity agents. Preferable examples of tonicity agents include sodiumchloride, glycerin, sodium bisulfite, benzalkonium chloride, fluctose,citric acid, sodium citrate, sodium dihydrogen phosphate (crystal),sodium hydroxide, D-sorbitol solution, nicotinic-acid amide,concentrated glycerin, propylene glycol, benzyl alcohol, boric acid,borax, macrogol 4000, sodium hydrogen phosphate, potassium dihydrogenphosphate, and sodium dihydrogen phosphate. Examples of suspendingagents include crystalline cellulose-sodium carmellose and hydroxypropylcellulose.

A gel preparation (suspension base) may be a hydrous gel, an anhydrousgel, or a gel with a low water content comprising a gel-forming materialthat can swell. It may also be a hydrogel base or a lyogel base, andpreferably a transparent hydrogel having an inorganic or organic polymeras abase. Similar to preparations comprising an oil or fat content, thegel itself is not absorbed by the nasal mucous membrane. Hydrogel baseshave no fat and a consistency similar to that of ointment preparation,and aim at increasing the percutaneous absorbability of drugs. Lyogelbases are gelled by suspending stearyl alcohol, etc. in propyleneglycol, and they have excellent absorbability by the nasal mucousmembrane and hygroscopicity.

The gel preparation of the present invention may be a gel preparationmade by homogenously dispersing CNP or BNP as an active ingredient intoa hydrophilic gel base comprising carboxy vinyl polymer, sodiumpolyacrylate, sodium polyacrylate, (vinyl methyl ether/ethyl maleate)copolymer, polymethacrylate, propylene glycol, etc.

A liquid preparation means those wherein an active ingredient consistingof CNP or BNP is dissolved in a base such as alcohol, propylene glycol,polyethylene glycol or water. Preferably, it means a liquid preparationconsisting of an aqueous solution wherein either CNP or BNP is dissolvedin saline. In the aqueous solution preparations, a small amount of anorganic base such as alcohol, propylene glycol, polyethylene glycol,etc. may be mixed, in addition to the saline.

An ointment preparation may comprise either a grease base or awater-soluble base, and both can be easily obtained in accordance withheretofore known methods. A grease base such as vaseline causes littleirritation and is odorless, which is superior in protective action ofthe nasal mucous membrane. Water-soluble bases produce ointmentpreparations having a macrogol base as the main ingredient, and theyhave a strong action to absorb and remove aqueous discharges.

A cream preparation (emulsion base) may be an oil-in-water base (O/W)(vanishing cream) or a water-in-oil base (cold cream). An oil-in-waterbase has a smaller amount of oil-soluble component than water-solublecomponent, so that it has an advantage that the white color of the creamappears to disappear upon application. In addition, since it is easilyabsorbed by the nasal mucous membrane, it can be very applicable tochronic hypertrophic lesions.

A lotion preparation means a liquid external preparation wherein CNP orBNP is dissolved or homogeneously dispersed in a liquid. Since lotionpreparations are in a liquid state, they are suitable for use in themucous membrane of the nasal cavities. The form of the lotionpreparations may be a suspended lotion base and an emulsion lotion.

A spray preparation refers to those wherein CNP or BNP is made into asolution, which is then sprayed by gas pressure. Sprays are convenientfor application to a wide area.

As a liquid preparation, for example an aqueous solution wherein anappropriate amount of CNP or BNP is blended, saline can be used.Alternatively, an aqueous solution wherein CNP or BNP is dissolved in abuffer that can retain CNP or BNP in a stable manner can be used.

As a powder preparation, CNP or BNP can be administered in a pure dosageform or a dosage form wherein CNP or BNP is diluted with an inactivecarrier. As inactive carrier, calcium carbonate or lactose can be used.At the same time, povidone and lactose can be added as a hydrophilicaid. Since the nose has a potent discharge mechanism, administration inthe form of dry powder is advantageous over liquid forms, because theduration of action is prolonged. Powders can be prepared by making finepowders through recrystallization, granulation, drying, or pulverizationto a specific grain size.

Aerosol preparations are prepared as follows: CNP or BNP is pulverizedto a size of preferably 5 μm or smaller, a dispersing agent is added ifnecessary, which is then filled in a spraying device together with apropellant while cooling. Examples of preferable dispersing agentsinclude nonionic surfactants commercially available under the brand nameof Span 80 and Span 85, amphoteric surfactants such as soybean lecithin,and natural alcohols such as oleyl alcohol. Preferable propellantsinclude fluorinated/chlorinated lower alkanes such as chlorofluorocarbon(CFC) 11, CFC 12, CFC 114 as well as mixtures thereof.

Thus, upon production of the therapeutic preparations for rhinitis ofthe present invention, various types of bases, moisturizing agents,ultraviolet absorbers, alcohols, chelates, pH adjusters, preservatives,thickening agents, coloring agents, flavors, filling agents, excipients,disintegrating agents, extenders, binding agents, film forming agents,solubilizers, suspending agents, buffers, stabilizing agents, preservingagents, surfactants, antioxidative agents, dispersing agents,emulsifying agents, dissolving agents, solubilizing agents, etc. may beblended in combination. Furthermore, in addition to the principal agentCNP or BNP, various drugs such as antiphlogistic analgesics, sterilizingagents and vitamins may be appropriately blended when necessary.

Examples of excipients include lactose, corn starch, calcium phosphate,etc. Examples of binding agents include crystalline cellulose, mannitol,hydroxypropyl cellulose, hydroxypropyl methylcellulose, macrogol, etc.

Preferable liquid preparations are CNP or BNP aqueous solutionpreparations comprised of an appropriate amount of CNP or BNP dissolvedin saline. It is possible to use a liquid preparation by filling aspraying device with it. These solution preparations may be blended withgeneral additives, for example, sedimentation-preventing agents such assorbitol, syrup, methylcellulose, gelatin, hydroxyl ethylcellulose,carboxy methylcellulose, aluminum stearate gel or hydrogenated food fat;emulsifying agents such as lecithin, sorbitan monooleate, and gumarabic; oily esters such as almond oil, purified coconut oil, andglycerin esters; nonaqueous media (which may include food oils) such aspropylene glycol and ethyl alcohol; preservatives such as p-hydroxylbenzoic acid methyl ester, ethyl ester or propyl ester, or sorbic acid;and if necessary, general flavoring agents or coloring agents.

Here, when oral preparations of the present therapeutic preparation forrhinitis are to be produced, it is preferable to make enteric-coateddrugs by coating the surface of the tablets or granules with an entericcoat, or by using enteric-coated capsules, in order to suppressdisintegration of the peptide CNP or BNP by gastric acid.

Moreover, solutions may be made into, in addition to the above-mentionedaqueous solutions, aqueous or oily suspension preparations or emulsionpreparations. Alternatively, they can be provided as dry pharmaceuticalcompositions, which can be re-dissolved into water or an appropriatemedium prior to their use.

Thus, the therapeutic preparation for rhinitis of the present inventionis a preparation made by blending an appropriate amount of CNP or BNPwith various bases, as well as additives if necessary. Dosage form andbase of the therapeutic preparation for rhinitis of the presentinvention can be appropriately selected depending on the symptoms andpatient.

Next, production of aqueous-solution preparations as liquidpreparations, and of gel preparations is described as representativeexamples of the present therapeutic preparations for rhinitis.

In the present invention, one preferred nasal drop preparation is anaqueous solution preparation. Such an aqueous solution preparation canbe prepared as follows: for example, 0.1-1 mg of human CNP-22 (PeptideInstitute, Inc.) as the principal agent is dissolved in 10 ml of salineto prepare the aqueous solution preparation with a CNP concentration of10-100 μg/ml. Here, since the specific gravity of water is 1, the CNPconcentration in this case is 10-100 μg/g by weight. The effect isinsufficient when the CNP concentration is 20 μg/ml or less, but it issufficient when the CNP concentration is 100 μg/ml; accordingly, it isnot necessary to use a concentration exceeding 200 μg/ml. Preferable CNPconcentration in aqueous solutions is 10-500 μg/g, more preferably20-200 μg/g, furthermore preferably 50-200 μg/ml, and particularlypreferably 50-100 μg/ml.

BNP aqueous solutions can be produced similarly to the CNP aqueoussolution preparations, and preferable concentrations are the same asthose of CNP aqueous solutions.

Gel preparations can be obtained by, in accordance with heretofore knownor well-known methods, dissolving an appropriate amount of CNP intodistilled water or saline to make an aqueous solution, and by mixing andstirring a heretofore known or well-known or commercially-availablegelling agent with the solution. Preferable CNP concentrations in thegel preparations are 10-500 μg/g, more preferably 20-200 μg/g,furthermore preferably 50-200 μg/g, particularly preferably 10-100jig/g, and even furthermore preferably 50-100 μg/g, and most preferably30-100 μg/g.

Examples of the gelling agents consisting of macromolecular inorganiccomponents include hydrous or water-absorbing silicates, such asaluminum silicate, for example bentonite, magnesium-aluminum silicate,and colloidal silica. As the gelling agent consisting of macromolecularorganic substances, natural, semi-synthetic, or synthetic polymers maybe used. Examples of natural and semi-synthetic polymers include,polysaccharides such as cellulose, starch, tragacanth, gum arabic,xanthan gum, agar-agar, gelatin, alginic acid and its salts, for examplesodium alginate and its derivatives, loweralkyl cellulose, for examplemethyl cellulose or ethyl cellulose, carboxy- or hydroxyl-lower-alkylcellulose, for example carboxymethyl cellulose, or hydroxypropylcellulose, etc.

Examples of synthetic gelling agents include polyvinyl alcohol,polyvinyl pyrrolidone, polyacrylic acid or polymethacrylic acid, etc.Only one kind of these gelling agents, or a mixture of two or more kindsof these may be used.

If necessary, a percutaneous absorption aid may be added. Examples ofthe percutaneous absorption aid include, for example, limonene, menthol,salicylic acid, hyaluronic acid, oleic acid, N,N-diethyl-m-toluamide,n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropylpalmitate, polypropylene glycol, crotamiton, diethyl sebacate, N-methylpyrrolidone, N-ethyl pyrrolidone, lauryl alcohol, etc. In addition, anantiseptic agent and an antioxidant may be added if necessary.

The concentration of CNP or BNP in the therapeutic preparation forrhinitis may be appropriately selected with consideration given tosymptoms, age, and dosage form, etc. Preferable concentrations of CNP orBNP are, for nasal drop preparations such as solutions, gelpreparations, lotion preparations, and aerosols, etc., 10-500 μg/g, andmore preferably 20-200 μg/g. For younger patients and patients withsensitive skin, those with a concentration of 20-100 μg/g are preferablyused. Preferable CNP or BNP concentrations in the gel preparations are10-100 μg/g, and particularly preferably 30-100 μg/g. Preferable CNP orBNP concentrations in the solutions are 20-200 μg/ml, and particularlypreferably 50-200 μg/ml.

The number of applications and the duration of application of thepresent therapeutic preparation for rhinitis differ depending onsymptoms, age and dosage form, etc.; normally, once or twice a day for 2to 7 days of application is sufficient.

Hereinafter, the present invention is explained with reference toexamples. However, the present invention is not limited to theseexamples.

Example 1

1. Production of CNP Nasal Solution:

A 1000 μg/ml CNP liquid preparation was prepared by dissolving 3 mg ofhuman CNP-22 (Peptide Institute, Inc.) as the principal agent in 3 ml ofsaline. 100 μl of the obtained 1000 μg/ml CNP solution preparation wasdiluted with 900 μl of saline to prepare the CNP nasal solutionpreparation with a CNP concentration of 100 μg/ml. Similarly, the CNPnasal solution preparation with a CNP concentration of 50 μg/ml wasprepared by diluting 50 μl of the 1000 μg/ml CNP solution preparationwith 950 μl of saline. Furthermore, similarly, the CNP nasal solutionpreparation with a CNP concentration of 200 μg/ml was prepared bydiluting 200 μl of the 1000 μg/ml CNP solution preparation with 800 μlof saline.

2. Production of Nasal Drop Preparations Consisting of CNP NasalSolution:

Three kinds of CNP nasal solution preparations with concentrations of100 μg/ml, 50 μg/ml, and 200 μg/ml obtained as above were used to fill ametered-dose nasal spraying device (Astellas Pharma, Inc.; ametered-dose nasal spraying device for Intal nasal solution was used),and the device was adjusted so that the amount of a solution deliveredby one spray is 130 μl. Accordingly, the amount of CNP contained in onespray of solution of the CNP nasal solutions with 100 μg/ml, 50 μg/ml,and 200 μg/ml are 13 μg, 6.5 μg, and 26 μg, respectively.

3. Production of BNP Nasal Solution Preparation:

A 1000 μg/ml BNP solution preparation was prepared by dissolving 3 mg ofhuman BNP-32 (Peptide Institute, Inc.) as the principal agent in 3 ml ofsaline. 100 μl of the obtained 1000 μg/ml BNP solution preparation wasdiluted with 900 μl of saline to prepare the BNP nasal solutionpreparation with a BNP concentration of 100 μg/ml. Similarly, the BNPnasal solution preparation with a BNP concentration of 50 μg/ml wasprepared by diluting 50 μl of the 1000 μg/ml BNP solution preparationwith 950 μl of saline. Furthermore, similarly, the BNP nasal solutionpreparation with a BNP concentration of 200 μg/ml was prepared bydiluting 200 μl of the 1000 μg/ml BNP solution preparation with 800 μlof saline.

4. Production of Nasal Drop Preparations Consisting of BNP NasalSolution:

Three kinds of BNP nasal solution preparations with concentrations of100 μg/ml, 50 μg/ml, and 200 μg/ml obtained as above were used to fill ametered-dose nasal spraying device (Astellas Pharma, Inc.; ametered-dose nasal spraying device for Intal nasal solution was used),and the device was adjusted so that the amount of a solution preparationdelivered by one spray is 130 μl. Accordingly, the amount of BNPcontained in one spray of solution for the BNP nasal solutionpreparations with 100 μg/ml, 50 μg/ml, and 200 μg/ml are 13 μg, 6.5 μg,and 26 μg, respectively.

5. Production of ANP Nasal Solution:

For comparative tests, a 500 μg/ml ANP solution preparation was preparedby dissolving 0.5 mg of human ANP-28 (Peptide Institute, Inc.) in 1 mlof saline. 1 ml of the obtained 500 μg/ml ANP solution was diluted with9 ml of saline to prepare the ANP nasal solution preparation with an ANPconcentration of 50 μg/ml.

6. Production of Nasal Drop Preparations Consisting of ANP NasalSolution:

The ANP nasal solution preparation with an ANP concentration of 50 μg/mlobtained as above was used to fill a metered-dose nasal spraying device(Astellas Pharma, Inc.; a metered-dose nasal spraying device for Intalnasal solution was used), and the device was adjusted so that the amountof a solution preparation delivered by one spray is 130 μl. Accordingly,the amount of ANP contained in one spray of solution is 6.5 μg.

Example 2

Diagnosis, evaluation of symptoms, and examination of the CNP nasal droppreparations, BNP nasal drop preparations and ANP nasal drop preparationwere performed as follows.

1. Subjects and Diagnosis

The subjects are patients in whom conventional external medicines suchas steroids are not sufficiently effective, or patients in whom the useof steroids must be avoided due to local side effects such as nasalirritation and dryness. Diagnosis and treatment of these subjects wereperformed by the present applicant as a medical doctor.

2. Evaluation of Symptoms

Severity evaluation of symptoms of allergic rhinitis was performed, inprinciple, in accordance with “Guidelines for medical care of nasalallergies, 2009 edition” (edited by the committee for creation ofguidelines for medical care of nasal allergies), by classifying into 5stages as shown below. Here, “mixed type” refers to the cases whereinboth of the sneezing attack or rhinorrhea and the nasal occlusion werepresented with the same severity.

TABLE 2 Degree and Sneezing attack or rhinorrhea (determined by itemwith higher score) severity − + 2+ 3+ 4+ Nasal 4+ Most severe Mostsevere Most severe Most severe Most severe occlusion (Nasal (Nasal(Nasal (Nasal (mixed occlusion occlusion occlusion occlusion type) type)type) type) type) 3+ Severe Severe Severe Severe Most severe (Nasal(Nasal (Nasal (mixed (sneezing/ occlusion occlusion occlusion type)rhinorrhea type) type) type) type) 2+ Moderate Moderate Moderate SevereMost severe (Nasal (Nasal (mixed (sneezing/ (sneezing/ occlusionocclusion type) rhinorrhea rhinorrhea type) type) type) type) + MildMild Moderate Severe Most severe (Nasal (mixed (sneezing/ (sneezing/(sneezing/ occlusion type) rhinorrhea rhinorrhea rhinorrhea type) type)type) type) − No Mild Moderate Severe Most severe symptoms (sneezing/(sneezing/ (sneezing/ (sneezing/ rhinorrhea rhinorrhea rhinorrhearhinorrhea type) type) type) type)

In the above table, evaluation scores for sneezing fit, rhinorrhea andnasal occlusion are as described in the table below.

TABLE 3 − + 2+ 3+ 4+ Sneezing 0 1-5 6-10 11-20 21 or more attack(average number of sneezing attacks per day) Nasal drip 0 1-5 6-10 11-2021 or more (average number of nose blows a day) Nasal 0 No mouth StrongVery strong Nose is occlusion breathing, occlusion, occlusion,completely but with breathing with mouth occluded nasal with thebreathing all day. occlusion mouth for a several considerable times aday amount of time a day Degree of 0 Almost no Between Cannot haveNormal disturbance disturbance (+) and normal daily daily life is indaily (3+) life because impossible life of disturbance3. Test Method of Nasal Solution Preparation

Administration tests of the nasal solution preparations of the presentinvention were performed by, in principle, spraying the CNP nasalsolution, BNP nasal solution or ANP nasal solution used to fill a nasalspraying device twice a day at awakening time and before bedtime, withone spray in each nostril at each time. Accordingly, the amount ofapplication of CNP, BNP or ANP per one spray for the 100 μg/ml CNP nasalsolution, BNP nasal solution, and ANP nasal solution corresponds to 13μg. Similarly, the amounts of application of CNP, BNP or ANP per onespray for the 50 μg/ml and 200 μg/ml CNP/BNP/ANP solutions correspond to6.5 μg and 26 μg, respectively.

Example 3

Diagnosis of Each Case

Prior to the application of CNP preparations, BNP preparations or ANPpreparation, the subjects' history was obtained, scratch tests forallergens were performed and diagnosis was made. Tables 4-7 show theresults of the subjects' history taking, diagnosis, i.e., sex, age, pasthistory, family history, scratch test result, diagnostic finding, andsymptom evaluation of the subject in each case.

Example 4

CNP Dosage-Finding Study

The after-mentioned subject of Case 10 was enrolled in the study, andthe 100 μg/ml CNP nasal solution was applied once a day for 7 daysconsecutively, then after 14 days of discontinuation, the 50 μg/ml CNPnasal solution was tested. As a result, the time required for themanifestation of the effect is approximately 20 min, that is, comparedto the 100 μg/ml CNP nasal solution, approximately twice as long a timeis required for the manifestation of the drug efficacy, with a slightlylower degree of improvement of nasal occlusion. Here, the 200 μg/ml CNPnasal solution showed significant effects on rhinitis withoutirritation, but the effects were not doubled compared to the case of 100μg/ml CNP nasal solution.

BNP Dosage-Finding Study

A dosage-finding study was also performed for BNP, and results similarto those for CNP were obtained.

Example 5

Results of administration of CNP preparations are summarized in Tables 4and 5 and FIG. 2, and details are described below as test examples 1-10.

TABLE 4 Case 1 Case 2 Case 3 Case 4 Case 5 Sex Female Female Female MaleFemale Age 48 years old 39 years old 32 years old 23 years old 24 yearsold Severity Severe Severe Severe Severe Severe level Disease type MixedSneezing/rhinorrhea Mixed Nasal occlusion Mixed Family Child; atopicChild; atopic Mother; atopic Mother; atopic Younger sister; historydermatitis, dermatitis dermatitis dermatitis atopic dermatitis allergicrhinitis Past history Atopic dermatitis Atopic dermatitis Atopicdermatitis Child asthma Atopic dermatitis Scratch test House dust: 3+House dust: 2+ House dust: 1+ House dust: 3+ House dust: 3+ Mite: 3+Mite: 2+ Mite: 1+ Mite: 3+ Mite: 3+ Cedar: — Cedar: 2+ Cedar: 1+ Cedar:— Cedar: 3+ Orchard grass: — Orchard grass: 3+ Orchard grass: 2+ Orchardgrass: — Orchard grass: 2+ Ragweed: — Ragweed: 1+ Ragweed: 1+ Ragweed: —Ragweed: 2+ Diagnostic finding Nasal drip (11-20) A lot of nasal drip,(11-20) (1-5) (11-20) (average so she uses a pile number of of tissuepaper for nose blows a nose blowing day) (approx. 20) Nasal Very strongnasal No mouth breathing, Very strong nasal Very strong nasal Verystrong nasal occlusion occlusion, with but has nasal occlusion, andocclusion, with occlusion, with mouth breathing occlusion. she is unableto mouth breathing mouth breathing for for a considerable smell well.for a considerable a considerable amount of time a amount of time aamount of time a day. day. day. Effects of Not used due to Nasalirritation, Nasal irritation, and Not used because of Not used due tonasal steroid nasal irritation. itching, sneezing, dryness sensationwithdrawal irritation and nasal spray and rhinorrhea as if the nose isdifficulty due to dryness. rather worsened, in contact with long termuse of and no subjective the back of the systemic steroids. improvementthroat existed; noticed. no satisfactory effects. Dosage form CNP nasalsolution CNP nasal solution CNP nasal solution CNP nasal solution CNPnasal solution preparation preparation preparation preparationpreparation Dosage 100 μg/ml 100 μg/ml 100 μg/ml 100 μg/ml 100 μg/mlNumber of Morning + before Once in the Once in the Once a day Once a daynasal bedtime morning morning applications Number of 2 days 3 days 7days 4 days 1 day days applied Symptom 15 min later, Nasal itching 5 minlater, nasal 5 to 10 min later, 20 min later, nasal improvementrhinorrhea was disappeared occlusion nasal occlusion occlusion sensationby initial relieved and immediately after disappeared and sensation wasimproved and nasal nasal occlusion spraying, and rhinorrhea wasdisappeared. rhinorrhea was application was improved. rhinorrhea wasrelieved. relieved. relieved 10 min later. Progress and Symptoms reducedThe sinus was not Nasal occlusion The effects lasted Both rhinorrhea andsymptom by spraying twice congested and sensation all day, and the nasalocclusion were improvement a day for 2 days rhinorrhea stoppeddisappeared by nasal passages alleviated for one including the byapplication continuous opened and the day. application at the once aday. The application once a subject was able to first visit, and botheffects lasted all day in the morning, breathe easily. rhinorrhea andday. After and rhinorrhea was After 4 days of nasal occlusiondiscontinuation of completely application, the were markedly theapplication, relieved 3 days application was improved. The effectslasted for later. After discontinued, but effects lasted 2-3 days, andcontinuous the effects lasted for 2-3 days after watery nasal dripapplication once for approximately discontinuation was suppressed. a dayfor one week, 3 days thereafter. of the application, application waswithout symptoms. discontinued, but the effects were maintained for along time thereafter. Symptom Severe → mild Severe → mild Severe → mildSevere → mild Severe → mild improvement

TABLE 5 Case 6 Case 7 Case 8 Case 9 Case 10 Sex Female Female FemaleMale Female Age 37 years old 39 years old 39 years old 21 years old 55years old Severity Severe Severe Moderate Severe Severe level Diseasetype Mixed Mixed Mixed Nasal occlusion Mixed Family Mother and elderChild; atopic None Mother; atopic Child; atopic history sister; atopicdermatitis dermatitis dermatitis dermatitis Past history Atopicdermatitis Atopic dermatitis Child asthma, Atopic dermatitis, Atopicdermatitis atopic dermatitis, allergic sinusitis conjunctivitis Scratchtest House dust: 3+ House dust: — House dust: 2+ House dust: 2+ Housedust: 1+ Mite: 3+ Mite: 2+ Mite: 3+ Mite: 3+ Mite: 2+ Cedar: — Cedar: —Cedar: 2+ Cedar: 2+ Cedar: 2+ Orchard grass: — Orchard grass: 3+ Orchardgrass: 1+ Orchard grass: 3+ Orchard grass: 3+ Ragweed: — Ragweed: —Ragweed: — Ragweed: 1+ Ragweed: 2+ Cat hair: 3+ Diagnostic finding Nasaldrip (11-20) (11-20) (6-10) (1-5) (11-20) (average number of nose blowsa day) Nasal Very strong nasal Very strong nasal Strong nasal Verystrong nasal Strong nasal occlusion occlusion, with occlusion, withocclusion, with occlusion, with occlusion, always mouth breathing mouthbreathing mouth breathing mouth breathing for having aural for aconsiderable for a considerable several times a day. a considerablefullness. amount of time a amount of time a amount of time a day. day.day. Effects of Not used due to Not used due to Not used because Hasused in the Nasal occlusion did steroid nasal irritation. nasalirritation, she suffered from past, but nasal not improve nasal spraysneezing and runny sinusitis 1.5 years occlusion did not sufficientlyand nose. ago. improve sufficiently. effects did not last for a longtime. Dosage form CNP nasal solution CNP nasal solution CNP nasalsolution CNP nasal solution CNP nasal solution preparation preparationpreparation preparation preparation Dosage 100 μg/ml 100 μg/ml 100 μg/ml100 μg/ml 100 μg/ml Number of Morning + before Once a day Once a dayOnce a day Once a day nasal bedtime (2 times) applications Number of 5days 1 day 1 day 1 day 7 days days applied Symptom 1 hr later, nasalNasal passages Nasal passages Nasal passages 10 min later, nasalimprovement occlusion was opened immediately opened immediately openedimmediately occlusion and runny by initial markedly after the after theafter the nasal nose completely nasal improved and she application andapplication and application and stopped. Aural application could breathenasal occlusion was nasal occlusion was rhinorrhea and fullness alsoeasily and sleep markedly improved markedly improved nasal occlusiondisappeared. well. 10 min later. 10 min later, nasal were markedly dripstopped 20 min improved 25 min later. later, then rhinorrhea stopped.Progress and By application By application once By application once Theeffects lasted The effects lasted symptom once a day, nasal a day,effects a day, effects all day by all day by improvement itching and alasted until the lasted until the application once in application once anasal occlusion next day and next day, and the late afternoon, day andnasal sensation improvement in rhinorrhea and and for 3 days symptomsstayed disappeared and rhinorrhea and nasal occlusion thereafter, runnyimproved, with she no longer nasal occlusion was were improved to a nosereduced to a watery nasal drip needed to blow her maintained.barely-troublesome barely-troublesome stopped and nasal nose. Afterlevel. level without any passages feeling application treatment. Duringopen. After twice a day, in the this period, internal discontinuation ofmorning and application of the application, the before bedtimeantihistamine effects lasted for for a total of 5 days, drugs was notapproximately 1 the application was necessary. week. discontinued, butthe effects lasted for 4-5 days. Symptom Severe → mild Severe → mildModerate → mild Severe → mild Severe → mild improvement

Test Example 1 (Case 1)

The subject is a 48-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher child also suffers from atopic dermatitis and allergic rhinitis.Scratch test results are: house dust 3+ and mite 3+. She has very strongnasal occlusion, with mouth breathing for a considerable amount of timea day, and also has strong watery nasal drip. She is unable to usesteroid nasal sprays due to nasal irritation.

As a preliminary test, the CNP nasal solution with a concentration of100 μg/ml obtained in Example 1 was sprayed once into each nostril ofthe subject (the amount of CNP administered to one nasal cavity was 13μg). As a result, 15 min later, rhinorrhea was relieved and nasalocclusion was improved. Permeability of the CNP nasal solution was goodwithout nasal irritation, and side effects such as local irritationsymptoms were not observed.

Therefore, in the morning and before bedtime on the next day (a total oftwo times), the present CNP nasal solution was sprayed once in eachnostril, then the symptoms reduced and rhinorrhea and nasal occlusionwere markedly improved for the whole day of day 3. After discontinuationof the nasal spray, the effects persisted for 2-3 days without symptoms.

Test Example 2 (Case 2)

The subject is a 39-year-old female who is a patient with severesneezing/rhinorrhea-type rhinitis. She has a past history of atopicdermatitis, and her child also suffers from atopic dermatitis. Scratchtest results are: house dust 2+, mite 2+, cedar 2+, orchard grass 3+,and ragweed 1+. She is a severe case having both symptoms of nasalocclusion, with sneezing and watery nasal drip requiring a pile oftissue paper, and is taking second-generation antihistamine drugs everyday. With steroid nasal sprays, nasal irritation, nasal itching,sneezing and rhinorrhea become worsened, and subjective effects ofimprovement are not noted. Similar to test example 1, the CNP nasalsolution with a concentration of 100 μg/ml obtained in Example 1 wassprayed once into each nostril of the subject (the amount of CNPadministration in one nasal cavity was 13 μg). As a result, nasalitching disappeared immediately after the spraying, and rhinorrhea wasrelieved after 10 min. The CNP nasal solution had a good permeabilitywithout nasal irritation, and no local side effects were observed. Byuse only once a day, the nose was not congested and absolutely norhinorrhea was observed. The effects lasted for a whole day.

Also on the next morning, absolutely no rhinorrhea was observed. To besafe, the present CNP nasal solution was sprayed once into each nostrilin the morning. As a result, the nose was not congested and norhinorrhea was observed during this day. She said that she almost hadforgotten about rhinitis, and second-generation antihistamine drugs hadnot been necessary.

These results demonstrated that the CNP nasal solution of the presentinvention is superior in persistence, absorbability and fast-actingproperty, and that sufficient effects can be obtained by spraying onlyonce a day.

Test Example 3 (Case 3)

The subject is a 32-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher mother also suffers from atopic dermatitis. Scratch test resultsare: house dust 1+, mite 1+, cedar 1+, orchard grass 2+, and ragweed 1+.This subject has a very strong nasal occlusion, and is unable to smell.She also has severe watery rhinorrhea. Steroid nasal spray induced nasalirritation and dryness sensation as if the nose was in contact with theback of the throat, and no satisfactory effects were obtained exceptthat runny nose slightly reduced after the application.

Similar to test example 1, the CNP nasal solution with a concentrationof 100 μg/ml obtained in Example 1 was sprayed once into each nostril ofthe subject (the amount of CNP administered in one nasal cavity was 13μg). As a result, the nasal occlusion sensation disappeared andrhinorrhea was relieved 5 min later. No local irritation symptoms wereobserved. Thereafter, spraying once a day in the morning was continued,then nasal occlusion sensation disappeared and she became able to smell,watery nasal drip was improved, and rhinorrhea was completely relieved 3days later. No local side effects such as irritation, as well as nosystemic side effects such as drowsiness were observed. For a week, theeffects lasted for the whole day by application once in the morning; ananti-allergic agent was orally taken on day 1, but this administrationwas not necessary from day 2 and thereafter. Application wasdiscontinued after one week, but the effects lasted for more than 2weeks thereafter. This finding demonstrated that the CNP nasal solutionof the present invention is excellent in fast-acting property,absorbability and persistence, and that sufficient effects can beobtained by spraying only once a day.

Test Example 4 (Case 4)

The subject is a 23-year-old male who is a patient with severenasal-occlusion-type rhinitis. He has a past history of childhoodasthma, and his mother suffers from atopic dermatitis. Scratch testresults are: house dust 3+, and mite 3+. This subject has a very strongtendency of nasal occlusion, with mouth breathing for a considerableamount of time a day. In addition, because of the withdrawal difficultysymptoms due to long-term use of systemic steroids, this subject mustavoid the use steroids.

Similar to test example 1, the CNP nasal solution with a concentrationof 100 μg/ml obtained in Example 1 was sprayed once into each nostril ofthe subject (the amount of CNP administration in one nasal cavity was 13μg). As a result, nasal occlusion sensation disappeared within 5 to 10min. The effects lasted for one day, and he was able to breathe easilywith open nasal passages. After the application of once a day for 4days, the application was discontinued, but the effects lasted for about3 days thereafter.

Similar to the above test cases, the CNP nasal solution has a goodpermeability without irritation or local side effects. These facts arealso observed in the following test examples.

Thus, the CNP nasal solution of the present invention has remarkableeffects, and can be a great relief for patients with rhinitis who mustavoid the use of steroid preparations.

Test Example 5 (Case 5)

The subject is a 24-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher younger sister also suffers from atopic dermatitis. Scratch testresults are: house dust 3+, mite 3+, cedar 3+, orchard grass 2+, andragweed 2+. The subject goes through mouth breathing for a considerableamount of time a day, and has a very strong tendency of nasal occlusion,with severe nasal drip. She dose not use steroid nasal sprays because ofnasal irritation and dryness.

Similar to test example 1, the CNP nasal solution with a concentrationof 100 μg/ml obtained in Example 1 was sprayed once into each nostril ofthe subject (the amount of CNP administered in one nasal cavity was 13μg). As a result, nasal occlusion sensation was improved 20 min later,and rhinorrhea was relieved. The effects lasted for one day, andalleviation of the nasal occlusion and rhinorrhea persisted on the nextday and thereafter.

Test Example 6 (Case 6)

The subject is a 37-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher mother and elder sister also suffer from atopic dermatitis. Scratchtest results are: house dust 3+ and mite 3+. This subject has, similarto Case 5, mouth breathing for a considerable amount of time a day, andhas a very strong tendency of nasal occlusion, with severe nasal drip.The subject was suffering from strong nasal occlusion and sneezing atnight, as well as nasal itching. She dose not use steroid nasal spraysbecause of nasal dryness.

The CNP nasal solution with a concentration of 100 μg/ml obtained inExample 1 was sprayed once into each nostril of the subject beforebedtime (the amount of CNP administration in one nasal cavity was 13μg); 1 hr later, nasal occlusion was markedly improved and she was ableto breathe easily and sleep well with well-opened nasal passages even inthe early hours of the morning, so she reported.

Moreover, the CNP nasal solution of the invention is re-sprayed onceinto each nostril on the next morning, following the administrationprevious night, then nasal itching and nasal occlusion sensationdisappeared for the whole day. Watery nasal drip was improved to acondition in which blowing of nose was not required. No local irritationsymptoms were observed. Thereafter, because the symptoms had stabilizedby the twice a day application for 5 days, the application wasdiscontinued. The effects persisted for 4-5 days after thediscontinuation, and the improved states of nasal itching, nasalocclusion and rhinorrhea were maintained.

Test Example 7 (Case 7)

The subject is a 39-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher child also suffers from atopic dermatitis. Scratch test results are:house dust −, mite 2+, cedar −, orchard grass 3+, and ragweed −. Thissubject, similar to Case 6, breathes through her mouth for aconsiderable amount of time a day, and has a very strong tendency ofnasal occlusion, with severe nasal drip. In particular the subject wassuffering from severe rhinorrhea, nasal occlusion and sneezing in theearly hours of the morning, as well as nasal itching. She had nasalirritation against steroid nasal sprays, and because sneezing and runnynose rather worsened, she was unable to use steroids; when she orallytook second-generation antihistamine drugs, she tends to feel sluggish;therefore, the use of antihistamine drugs must be avoided as much aspossible.

Under such conditions, the CNP nasal solution with a concentration of100 μg/ml obtained in Example 1 was sprayed once into each nostril ofthe subject (the amount of CNP administered in one nasal cavity was 13μg); immediately after spraying, the nasal passages opened, and thenasal occlusion was markedly improved after 10 min. She also reportedthat she was able to breathe easily. Watery nasal drip, that hadcontinuously discharged if the nostrils were not packed with tissuepaper, stopped. With an application once a day, the effects lasted untilthe next day, and the improvements in nasal occlusion and rhinorrheawere maintained.

Thus, the CNP nasal solution of the present invention is a relief forrhinitis patients with whom the use of conventional steroids andantihistamine drugs should be avoided or inapplicable.

Test Example 8 (Case 8)

The subject is a 39-year-old female who is a patient with moderatemixed-type rhinitis. She has a past history of atopic dermatitis,childhood asthma and sinusitis, but her family members do not sufferfrom any of these diseases or allergic rhinitis. Scratch test resultsare: house dust 2+, mite 3+, cedar 2+, orchard grass 1+, ragweed −, andcat hair 3+. This subject goes through mouth breathing several times aday, and has a strong tendency of nasal occlusion. She did not usesteroids because she had suffered from sinusitis one and half years ago.

The CNP nasal solution with a concentration of 100 μg/ml obtained inExample 1 was sprayed once into each nostril of this subject (the amountof CNP administered in one nasal cavity was 13 μg); as a result, thenasal passages opened immediately after spraying, and the nasalocclusion was markedly improved after 10 min, so that she could breatheeasily. 20 min later, watery nasal drip stopped. Moreover, she reportedthat she could breathe easily.

The effects lasted for a whole day by application once a day, and bothnasal occlusion and rhinorrhea were improved to a barely-troublesomelevel.

Test Example 9 (Case 9)

The subject is a 21-year-old male who is a patient with severenasal-occlusion-type rhinitis. He has a past history of atopicdermatitis and allergic conjunctivitis, and his mother also suffers fromatopic dermatitis. Scratch test results are: house dust 2+, mite 3+,cedar 2+, orchard grass 3+, and ragweed 1+. This subject, similar toCase 7, breathes through his mouth for a considerable amount of time aday, and has a very strong tendency of nasal occlusion. He had usedsteroids in the past, but nasal occlusion was not improved sufficiently.Nasal drip was not so severe.

The CNP nasal solution with a concentration of 100 μg/ml obtained inExample 1 was sprayed once into each nostril of this subject (the amountof CNP administered in one nasal cavity was 13 μg); as a result,immediately after spraying, the nasal passages opened, and the nasalocclusion was markedly improved and rhinorrhea was relieved after 25 minwithout any irritation symptoms. As a result of nasal application ofonce at early evening, the effects lasted for one day and thereafterrunny nose almost reduced to a barely-troublesome level for 3 dayswithout any additional treatment, and blowing of his nose was hardlyrequired. During this time, internal administration of antihistaminedrugs was not necessary.

Test Example 10 (Case 10)

The subject is a 55-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher child also suffers from atopic dermatitis. Scratch test results are:house dust 1+, mite 2+, cedar 2+, orchard grass 3+, and ragweed 2+. Thissubject has a strong nasal occlusion, and always has aural fullness.Oral steroids and steroid sprays were applied to this subject threetimes a day, but the effects on the nasal occlusion were not sufficient,and the durability of the effects was poor, while improvement inrhinorrhea was insufficient. Upon application of steroid sprays, she hada headache with a feeling of heaviness from the back of the nose to thehead and drowsiness.

The CNP nasal solution with a concentration of 100 μg/ml obtained inExample 1 was sprayed once into each nostril of this subject (the amountof CNP administered in one nasal cavity was 13 μg); as a result, nasalocclusion and runny nose stopped completely without irritation symptomsafter 10 min. Thereafter, the CNP nasal solution of the invention wasapplied twice in the morning and before bedtime without taking steroidsinternally, then nasal occlusion and rhinorrhea were markedly improved,and aural fullness also disappeared. The effects lasted for a whole daywith application once daily thereafter, and nasal symptoms were markedlyimproved, with runny nose stopped and nasal occlusion suppressed with afeeling of open nasal passages. It was not necessary to use internalsteroids or injections which had previous been continuously used. Theapplication was discontinued after 7 days of application of the 100μg/ml CNP nasal solution, but the effects lasted for approximately 1week and the condition of reduced nasal occlusion and rhinorrhea wasmaintained. After 14 days of discontinuation, the application of the 50μg/ml CNP nasal solution at an interval of once a day was started andcontinued for 5 days; then, nasal occlusion was relieved 20 min afterthe nasal spraying, and rhinorrhea was also improved to the level of 3to 4 times a day of nose blowing. Moreover, aural fullness haddisappeared. These effects lasted for 3-4 days after discontinuation ofthe application.

Example 6

The results of the use of BNP preparations are summarized in Table 6 andFIG. 3, and details are described below as test examples 11-16.

TABLE 6 Case 11 Case 12 Case 13 Case 14 Case 15 Case 16 Sex FemaleFemale Female Female Female Male Age 42 years old 21 years old 28 yearsold 46 years old 45 years old 35 years old Severity level Most severeModerate Most severe Most severe Severe Most severe Disease typeSneezing/ Mixed Nasal occlusion Mixed Sneezing/ Mixed rhinorrhearhinorrhea Family history Child; allergic Father; allergic Youngersister; Child; allergic Child; allergic Father, elder rhinitis, atopicrhinitis allergic rhinitis, rhinitis rhinitis, atopic sister, child;dermatitis atopic dermatitis, dermatitis allergic rhinitis Past historyAtopic dermatitis, Atopic dermatitis Atopic dermatitis Atopicdermatitis, Atopic dermatitis Allergic allergic allergic conjunctivitisconjunctivitis conjunctivitis Scratch test House dust: 2+ House dust: 1+House dust: 1+ House dust: 2+ House dust: 2+ House dust: − Mite: 2+Mite: 2+ Mite: 2+ Mite: 2+ Mite: 3+ Mite: 1+ Cedar: − Cedar: 3+ Cedar:3+ Cedar: 3+ Cedar: 1+ Cedar: 2+ Orchard grass: 3+ Orchard grass: 1+Orchard grass: 3+ Orchard grass: 3+ Orchard grass: 2+ Orchard grass: 3+Ragweed: 2+ Ragweed: 1+ Ragweed: 2+ Ragweed: 2+ Ragweed: 1+ Ragweed: 1+Diagnostic finding Nasal drip Constant (approx. 10) Runny nose doesConstant watery Watery nasal Watery nasal drip (average runny nose notstop all day rhinorrhea if drip discharges continuously number of nose(21 or more) (21 or more) the nostrils continuously and discharges sothat blows a day) were not packed perennially. he uses 2 boxes of (21 ormore) (approx. 20) tissue paper per day. (21 or more) Nasal occlusionHas mouth Due to strong Almost no mouth Fairly strong Almost no nasalCompletely breathing only nasal occlusion, breathing, but occlusion,with occlusion occluded all day. at night due to mouth breathing, hasnasal mouth breathing (less than +) nasal occlusion. at intervals ofocclusion. for a considerable the day. amount of time a day. Effects ofShe never felt At the time of She had Completely no She has strong Hetended to steroid nasal the effects, worsening of irritation witheffects by nasal irritation, show steroid spray/local having strongsymptoms, tight-stretched steroid nasal and watery nasal resistance, soside effects local dryness sufficient feeling of nasal solutions; dripincreases that steroids with pain. effects were not nucosa and havinglocal from that before became ineffective obtained by dryness; drynessthe nasal from the second steroid nasal therefore she had sensation.application. application. He application, no satisfactory also hadstrong especially for therapeutic irritation rhinorrhea. effects.symptoms. Dosage BNP nasal BNP nasal BNP nasal BNP nasal BNP nasal BNPnasal form solution solution solution solution solution solutionpreparation preparation preparation preparation preparation preparationDosage 50 μg/ml 50 μg/ml 100 μg/ml 50 μg/ml 200 μg/ml 50 μg/ml Number ofOnce in the Twice in the Once in the Once before Once a day Once in thenasal morning, or twice morning and at morning bedtime morning, or twiceapplications in the morning night in the morning and at night and atnight Number of 5 days 7 days 1 day 4 days 2 days 5 days days appliedSymptom 10 min later, the Watery Runny nose The nose felt Nasal dripWatery nasal improvement by BNP solution rhinorrhea stopped 30 relieved5 min stopped 10 min drip and itching initial nasal permeated thestopped 10 min min later. later, and nasal later. She had stopped 10 minapplication nasal mucosa and later and nasal Sneezing also passagesopened no irritation and later. No irritation symptoms occlusion stopped1 hr 15 min later, no uncomfortable symptoms. reduced and sensationafter the nasal with marked feeling. watery nasal improved 20 minspraying. improvement in drip was later. rhinorrhea; improved. nasalocclusion was markedly improved 30 min later and itching in the throatwas also relieved. Progress and Symptoms can be As a result of Theeffects By nasal Without combined By application symptom relived bycontinuous lasted for half spraying once use of internal twice in theimprovement application application a day thereafter, before bedtime,antihistamine morning and once or twice a twice a day for 1 and a runnynose the effects drugs, the night, nasal day. week, watery began atabout 9 lasted for 3-4 effect of the occlusion was Absolutely norhinorrhea and o'clock at night. days; thereafter stoppage of improved,and local irritation nasal occlusion application nasal drip internaladmini- symptoms. were improved; once before lasted all day, stration ofanti- therefore, the bedtime every and watery nasal histamine drugsapplication was 3-4 days drip could be was unnecessary. discontinued.maintained the relived by After Thereafter, the condition withapplication once discontinuation symptoms did not improved a day thenext of the application, reappear for 4-5 rhinorrhea, day. the effectsto days, and a nasal occlusion relieve rhinorrhea reduced state anditching of and nasal occlusion was maintained. the eyes. lasted for 7days. Symptom Most severe → Moderate → Most severe → Most severe →Severe → Most severe → improvement mild mild mild moderate mild mild

Test Example 11 (Case 11)

The subject is a 42-year-old female who is a patient with most severesneezing/rhinorrhea-type rhinitis. She has a past history of atopicdermatitis and allergic conjunctivitis, and her child suffers fromallergic rhinitis and atopic dermatitis. Scratch test results are: housedust 2+, mite 2+, cedar −, orchard grass 3+, and ragweed 2+. Thissubject breathes through her mouth only at night due to nasal occlusion.This subject has suffered from atopic dermatitis since infancy, and alsohad a pollen allergy since she was 22-23 years old. Her symptoms worsenfrom May to early July every year. During this period, she sneezesconstantly and has a runny nose. She does not feel any effects fromsteroid nasal sprays, and only experiences a strong dryness sensationwith a pain as local irritation symptoms.

As a trial, the BNP nasal solution with a concentration of 50 μg/mlobtained in Example 1 was sprayed only once into each nostril of thissubject (the amount of BNP administered in one nasal cavity was 6.5 μg);then 10 min later, the BNP nasal solution permeated the nasal mucousmembrane and the symptoms were relieved, and watery nasal drip wasimproved. Since these effects were confirmed, she went out under the sunafter spraying once in the morning on the 2nd day, and symptoms ofpollen allergy were improved to a barely-troublesome level, and runnynose and sneezing were not observed until early evening. For a period of5 days thereafter, she used the 50 μg/ml BNP nasal solution sprayingonce in the morning; on some days runny nose and sneezing did not occurall day, but on other days runny nose occurred in the afternoon; inthese cases, application twice a day could relieve the symptoms.Antihistamine drugs were not necessary. Moreover, local irritationsymptoms did not occur.

Test Example 12 (Case 12)

The subject is a 21-year-old female who is a patient with moderatemixed-type rhinitis. She has a past history of atopic dermatitis, andher father suffers from allergic rhinitis. Scratch test results are:house dust 1+, mite 2+, cedar 3+, orchard grass 1+, and ragweed 1+. Thissubject has suffered from atopic dermatitis since infancy, and alsopollen allergy since 2 years ago; she has itching with a ticklingsensation and rhinorrhea, nasal occlusion, which worsen particularlywhen she is tired. Nasal occlusion is strong and she goes through mouthbreathing several times a day. Nasal steroids did not show sufficienteffects on this subject at times of worsening of the symptoms,particularly on rhinorrhea.

As a trial, the BNP nasal solution with a concentration of 50 μg/mlobtained in Example 1 was sprayed only once into each nostril of thissubject (the amount of BNP administered in one nasal cavity was 6.5 μg);10 min later, watery rhinorrhea stopped and opening of the nasalpassages was slightly improved; nasal occlusion was improved 20 minlater. The next morning, by only one spray, the usual nasal itching andrunny nose were relieved after 10-20 min, and the nasal occlusionsensation reduced and the effects lasted until dinnertime. As a resultof use twice a day in the morning and at night for one week, wateryrhinorrhea and nasal occlusion were improved; accordingly theapplication was discontinued. Thereafter the effects lasted andrhinorrhea and nasal occlusion did not relapse for 4-5 days after thediscontinuation of the nasal application, maintaining the relievedcondition. The application of BNP nasal solution twice a day improvedthe symptoms from moderate to mild degree.

Test Example 13 (Case 13)

The subject is a 28-year-old female who is a patient with the mostsevere rhinorrhea-type rhinitis. She has a past history of atopicdermatitis, and her younger sister suffers from allergic rhinitis andatopic dermatitis. Scratch test results are: house dust 1+, mite 2+,cedar 3+, orchard grass 3+, and ragweed 2+. This subject has sufferedfrom atopic dermatitis since infancy, and symptoms of pollen allergybegan to appear since around 20 years of age. In particular, runny noseand sneezing became very severe from around June, and she constantlyblew her nose all day and runny nose was discharging when she bent herhead down. This subject rarely undergoes mouth breathing, but has anasal occlusion.

The BNP nasal solution with a concentration of 100 μg/ml obtained inExample 1 was sprayed only once into each nostril of this subject (theamount of BNP administered in one nasal cavity was 13 μg); then 30 minlater, runny nose stopped. Sneezing also stopped 1 hr after theapplication. Thereafter, the effects of the present nasal solutionlasted for half a day, and it was around 9 o'clock in the evening whenrunny nose began to discharge again. The degree of improvement insymptoms by the present BNP nasal solution was from a severe to a mildlevel.

Upon application of steroid nasal solutions or internal application ofsteroids, the subject had irritation such that the surface of her nasalmucous membrane felt tightly-stretched, as well as dryness as sideeffects, and accordingly satisfactory therapeutic effects had not beenobtained. In contrast, while the present BNP nasal solution showssuperior effects to steroids, it does not exhibit such side effects.

Test Example 14 (Case 14)

The subject is a 46-year-old female who is a patient with most severemixed-type rhinitis. She has a past history of atopic dermatitis andallergic conjunctivitis, and her child also suffers from allergicrhinitis. Scratch test results are: house dust 2+, mite 2+, cedar 3+,orchard grass 3+, and ragweed 2+. This subject has suffered from a runnynose, nasal occlusion and itching of the eyes since she was about 10years old, and from the age of 20, rhinitis has become more severe andrunny nose continuously discharged if the nostrils were not packed. Thissubject has a fairly strong nasal occlusion, and breathes through hermouth for a considerable amount of time a day.

The BNP nasal solution with a concentration of 50 μg/ml obtained inExample 1 was sprayed only once into each nostril of this subject (theamount of BNP administered in one nasal cavity was 6.5 μg); 5 min later,she felt that her nose became lighter, and that her nasal passagesopened after 15 min, with a marked improvement observed for rhinorrhea;the nasal occlusion sensation was markedly improved 30 min later, anditching of the throat was relieved. The subject was deeply moved by theefficacy of the present nasal solution.

In addition, according to the report by the subject, steroid nasalsolution showed not only irritation symptoms with a feeling of nasaldryness, but also no efficacy at all. In the case of the present nasalsolution however, it gave a rather moist feeling.

By spraying once before bedtime, she slept well without nasal drip,without taking oral antihistamine drugs. With application beforebedtime, rhinorrhea symptoms did not bother her during the daytime ofthe next day, blowing her nose only once every hour, and combinedinternal use of antihistamine drugs was not necessary. The effectslasted for 3-4 days by only one application before bedtime; thereafter,application of once before bedtime every 3-4 days, totaling 4 timeapplications, enabled maintenance of relieved conditions whereinrhinorrhea, nasal occlusion and itching of the eyes reduced to moderatelevels. The degree of improvement in symptoms by the BNP nasal solutionwas from a most severe to a moderate level.

Test Example 15 (Case 15)

The subject is a 45-year-old female who is a patient with severesneezing/rhinorrhea-type rhinitis. She has a past history of atopicdermatitis, and her child also suffers from atopic dermatitis andallergic rhinitis. Scratch test results are: house dust 2+, mite 3+,cedar 1+, orchard grass 2+, and ragweed 1+. This subject continuouslyhas perennial watery nasal drip, but has almost no nasal occlusion.Nasal application of steroid drops increased watery nasal drip, givingstrong nasal irritation.

The BNP nasal solution with a concentration of 200 μg/ml obtained inExample 1 was sprayed only once into each nostril of this subject (theamount of BNP administered in one nasal cavity was 26 μg); then 10 minlater, nasal drip stopped. At this time, she reported that she had nolocal irritation symptoms or feelings of discomfort. Without combinedinternal application of antihistamine drugs, the effect of stoppingnasal drip lasted all day. Watery nasal drip was suppressed by use oncea day on the next day. The degree of symptoms was improved from severeto mild by the use of the BNP nasal solution for 2 days.

Test Example 16 (Case 16)

The subject is a 35-year-old male who is a patient with the most severemixed-type rhinitis. He has a complication of allergic conjunctivitis,and his father, elder sister and child suffer from allergic rhinitis.Scratch test results are: house dust −, mite 1+, cedar 2+, orchard grass3+, and ragweed 1+. This subject has continuous watery nasal drip, sothat he has to use 2 boxes of tissue paper to blow his nose. He also hasnasal occlusion, and is in the condition of complete nasal stuffinessthe entire time. These symptoms have persisted from late May toSeptember. When nasal steroids are applied, he tends to have steroidresistance, so that the effect of the steroids cannot be attained fromthe second time use; moreover, he has strong irritation to the use ofsteroids.

The BNP nasal solution with a concentration of 50 μg/ml obtained inExample 1 was sprayed only once into each nostril of this subject (theamount of BNP administered in one nasal cavity was 6.5 μg); then 10 minlater, watery nasal drip, nasal itching, and nasal occlusion sensationswere relieved. At this time, no irritation symptoms were observed.Subsequently, spraying once in the morning for 5 days resulted indisappearance of nasal itching 10 to 15 min later, and watery nasal dripstopped, and these effects lasted for one day without runny nose all daylong. By use twice in the morning and at night, nasal occlusion wasimproved and internal use of antihistamine drugs became unnecessary. Thedegree of improvement in symptoms of a 5-day application period was frommost severe to mild. After discontinuation of the usage, relievingeffects of rhinorrhea and nasal occlusion were maintained for 7 days.

For comparison, tests were performed using ANP nasal solutions.

Example 7

Results of comparative examples using ANP preparations are summarized inTable 7, and details are described below as test examples 7-18.

TABLE 7 Case 17 Case 18 Case 2 (comparative example 1) (comparativeexample 2) (comparative example 3) Sex Male Female Female Age 28 yearsold 28 years old 40 years old Severity level Severe Severe SevereDisease type Mixed Mixed Sneezing/rhinorrhea Family history Father;atopic dermatitis, Mother; allergic rhinitis Child; atopic dermatitisallergic rhinitis Past history Atopic dermatitis Atopic dermatitisAtopic dermatitis Scratch test House dust: 2+ House dust: 2+ House dust:2+ Mite: 3+ Mite: 2+ Mite: 2+ Cedar: — Cedar: 2+ Cedar: 2+ Orchardgrass: 3+ Orchard grass: 3+ Orchard grass: 3+ Ragweed: 2+ Ragweed: 2+Ragweed: 1+ Diagnostic finding Nasal drip Severe runny nose and sneezing(11-20) Nasal drip is severe, so that (average number (Approx. 20) sheuses a pile of tissue paper of nose blows a for nose blowing. day)(Approx. 20) Nasal occlusion Nasal occlusion sensation Strong at night.No mouth breathing at all, but becomes strong in around June, has nasalocclusion. so he has mouth breathing. Effects of — Not used because ofnasal Nasal irritation, itching, steroid nasal irritation. sneezing andrhinorrhea spray conversely worsen, without subjective effects ofimprovement. Dosage form ANP nasal solution preparation ANP nasalsolution preparation ANP nasal solution preparation Dosage 50 μg/ml 50μg/ml 50 μg/ml Number of nasal Twice in the morning and at night Twicein the morning and at night Twice in the morning and at nightapplications Number of days 7 days 2 days 3 days applied Symptom Thenumber of nose blows reduced Rhinorrhea did not stop 15 min At 1 hrlater, a slight improvement by to approximately 10 times a day, later,but at 20 min later she improvement in nasal itching initial nasal butrunny nose and sneezing subjectively felt that nasal was observed, butwas not so application persisted, and nasal occlusion passages hadopened wider than apparent. Rhinorrhea was not sensation was notimproved. before the application. improved. Tickling feeling of the noseHowever, at 20 min thereafter, improved slightly. the nasal occlusionrelapsed and she felt nasal itching. Progress and ANP nasal solution wasused On the next morning, nasal After 3 days, only nasal itching symptomtwice a day for 7 days; however, occlusion was so strong that she wasmildly improved, but the improvement rhinorrhea and nasal occlusion wokeup due to the occlusion, persistence was low, and when were not improvedcompared to and she sprayed the ANP nasal the ANP solution was used inthe the state before the solution once, but nasal morning, the symptomsrelapsed application. occlusion relapsed 20 min in the afternoon. Noimprovement later. in rhinorrhea was observed, and she needed to blowher nose approximately 20 times a day. Symptom Severe → severe Severe →severe Severe → severe improvement

Comparative Example 1 (Case 17)

The subject is a 28-year-old male who is a patient with severemixed-type rhinitis. He has a past history of atopic dermatitis, and hisfather suffers from atopic dermatitis and allergic rhinitis. Scratchtest results are: house dust 2+, mite 3+, cedar −, orchard grass 3+, andragweed 2+. This subject has suffered from atopic dermatitis sinceinfancy, and symptoms of pollen allergy appeared since he began to work;nasal occlusion becomes strong particularly around June and he tends tobreathe through his mouth. Runny nose and sneezing are severe, and thenumber of times of nose blowing is approximately 20 times a day.

The ANP nasal solution with a concentration of 50 μg/ml obtained inExample 1 was sprayed twice a day into each nostril of this subject (theamount of ANP administered in one nasal cavity was 6.5 μg); however,runny nose and sneezing did not stop and the nasal occlusion sensationwas not improved. The ANP nasal solution was used twice a day for 7days, but no changes in rhinorrhea and nasal occlusion were observedbetween before and after the application, indicating no improvement. Thedegree of improvement in symptoms was from severe before the ANPapplication to still severe after the ANP application.

Comparative Example 2 (Case 18)

The subject is a 28-year-old female who is a patient with severemixed-type rhinitis. She has a past history of atopic dermatitis, andher mother also suffers from allergic rhinitis. Scratch test resultsare: house dust 2+, mite 2+, cedar 2+, orchard grass 3+, and ragweed 2+.This subject has perennial persistent rhinitis, which particularlyworsens between early summer and early autumn, with constant sneezingand watery nasal drips, and a strong nasal occlusion at night. Shereported that she does not use steroids because of nasal irritation.

The ANP nasal solution with a concentration of 50 μg/ml obtained inExample 1 was sprayed only once into each nostril of this subject (theamount of ANP administered in one nasal cavity was 6.5 μg); rhinorrheadid not stop 15 min later, but 20 min later she subjectively felt thatnasal passages opened compared to the condition before application.However, thereafter within approximately 20 min, nasal occlusionre-occurred, and she had a tickly sensation. The ANP nasal solution wasre-sprayed once at the night of the same day, and she subjectively feltthat nasal passages opened 20 min later, but nasal occlusion re-occurredwith a tickly sensation 15 min after the re-spraying. On the nextmorning, nasal occlusion was so strong it woke her up, so she sprayedthe ANP nasal solution once; however, 20 min later nasal occlusionre-occurred. The severity level and the degree of improvement were fromsevere to severe, showing no satisfactory improvement effects.

Comparative Example 3 (Case 2)

The subject is the same subject as the Case-2 subject in whom 100 μg/mlCNP nasal solution was tested. However, she was 40 years old when theANP nasal solution was tested, because 11 months had passed since theCNP nasal solution was applied for 3 days. Background informationincluding past history, family history, scratch test results, effects ofsteroids, etc. are the same as those described in test example 2 andTable 4.

The ANP nasal solution with a concentration of 50 μg/ml obtained inExample 1 was sprayed once into each nostril of this subject (the amountof ANP administered in one nasal cavity was 6.5 μg); however, noimmediate effect was observed. One hour later, a sign of slightimprovement in nasal itching was observed, but it was not clear, andrhinorrhea was not improved. The ANP nasal solution was applied on thenight of the same day, in the morning and at night of the next day andthe day after the next day similarly to that mentioned above; 3 dayslater, only nasal itching was slightly improved, but its persistence wasshort, and nasal itching re-occurred in the afternoon when the nasalsolution was used in the morning. No improvement in rhinorrhea wasobserved by application for 3 days, and she needed to blow her noseapproximately 20 times a day. The severity level and degree ofimprovement was from severe to still severe, showing no apparentimprovement effects.

Summary of the Results of Case Studies

As is clear from the above test examples, the nasal solutions of thepresent invention manifested their effects, at approximately 10 to 20min after spraying, on the representative symptoms of rhinitis, i.e.,nasal occlusion, sneezing attack and rhinorrhea. They are effective toany type of rhinitis including the mixed type, the nasal-occlusion type,and the sneezing/rhinorrhea type. Furthermore, the nasal solutions ofthe present invention including both the CNP nasal solutions and the BNPnasal solutions not only have remarkable effects of improvement inrhinitis, but also their manifestation of drug efficacy is extremelyfast, i.e., they are fast-acting, without local side effects such asirritation and systemic side effects such as drowsiness. They are alsolong-lasting, with excellent compliance of application of only 1-2 timesa day. Thus, the present nasal solutions have ideal characteristics asnasal drop preparations. In addition, a trend was observed that repeatedapplications result in an increase in the degree of improvement in somecases.

The nasal solutions of the present invention have more significanteffects than those of conventional steroids and antihistamine drugs, andthey are revolutionary drugs in terms of persistence, in that they canrelieve symptoms by application only once a day.

Moreover, since ANP and BNP share the same receptors, they were presumedto have identical effects; surprisingly, however, only BNP hadsignificant effects of the two, contrary to expectations.

We have conducted similar clinical tests with additional 10 cases; as aresult, extremely remarkable improvement effects of symptoms wereobserved in all the cases including many severe cases wherein internaladministration of anti-allergic agents and steroids could be terminatedthereby, it is worth noting that with the nasal solutions of the presentinvention, a drastic reduction in medical expenses can be expected, inaddition to their significant drug efficacy.

INDUSTRIAL APPLICABILITY

The therapeutic preparations for rhinitis of the present invention areextremely effective for the treatment of various types of rhinitis, inparticular allergic rhinitis, without a concern of causing side effects;thus, the present preparations are applicable to patients in whomconventional steroid nasal sprays and antihistamine drugs are noteffective, or patients who must avoid the use of these drugs due topossible side effects, as well as young patients.

Meanwhile, regarding the treatment of cedar pollen allergy, and forpatients with moderate to most severe cedar pollen allergy, thefollowing treatment is recommended according to the Allergic Rhinitisand Its Impact on Asthma (ARIA), 2008 edition: the treatment shouldstart with a steroid nasal spray alone, then the amount of the steroidnasal spray should be increased when no improvement is observed; and anantihistamine drug should be added for sneezing/nasal itching,ipratropium bromide hydrate should be added for rhinorrhea, and avasoconstrictive agent or an oral steroid should be added to nasalocclusion; that is, a step-wise treatment is recommended.

However, conventionally-used steroid nasal sprays are used with afrequency of 2-4 times a day for adults, of which effects only last forashort period and the time required for manifestation of the effects is1-3 days or more, requiring about 2 to 4 weeks before the maximum levelof effects is reached. The level of satisfaction with the effects islow. In addition, they have side effects such as nasal irritation,dryness, and irritation in the throat, headache, and a risk ofcomplication with infections due to long-term use.

Mometasone furoate hydrate, which has an advantage of spraying once aday, has become recently available in Japan; however, the effectsreported on pollen allergy in Europe and the United States after 2 weeksof application are as follows: the degree of improvement in overallsymptoms was 40-50%, the degree of improvement in nasal occlusion was30-40%; thus, they are not sufficient from the viewpoint of therapeuticeffects.

In contrast, the therapeutic preparations for rhinitis of the presentinvention can markedly improve severe rhinitis symptoms by applicationonly once a day, without internal administration of steroids andantihistamine drugs. In addition, the effects are fast-acting andlong-lasting. Namely, manifestation of the effects can be observedimmediately after the application, and in most cases both nasalocclusion and rhinorrhea are markedly improved 10-20 min after theapplication. Moreover, in all the cases, excellent improvement effectson nasal occlusion and rhinorrhea are maintained all day by onlyspraying once or twice a day.

Furthermore, local side effects observed in steroid nasal sprays are notat all manifested, and all the subjects reported that the presentpreparations are used quite comfortably. Systemic side effects such asdrowsiness and a decrease in working efficiency observed by internaladministration of antihistamine drugs and steroids are not present.Moreover, they have good compliance because their administrationfrequency is one spray at once or twice per day. Namely, the therapeuticpreparations for rhinitis of the present invention are superior overconventional nasal solutions in terms of the fast-acting andlong-lasting properties, are without side effects and have a goodcompliance; therefore they have ideal characteristics as a therapeuticpreparation for allergic rhinitis.

Accordingly, practical application of the therapeutic preparations forrhinitis of the present invention is very promising as a noveltherapeutic preparation for rhinitis that replaces conventional steroidsand antihistamine drugs.

The invention claimed is:
 1. A method of treating rhinitis, the methodcomprising applying a composition that comprises an effective amount ofC-type natriuretic peptide (CNP) to a nasal cavity or nostril of asubject in need of such treatment, wherein the CNP is selected from thegroup consisting of CNP-22 and CNP-53, wherein the amino acid sequenceof CNP-22 is SEQ ID NO: 1 and the amino acid sequence of CNP-53 is SEQID NO:22.
 2. The method of treating rhinitis according to claim 1,wherein the concentration of the CNP is 20-200 μg/g weight of thecomposition.
 3. The method of treating rhinitis according to claim 1,wherein the concentration of the CNP is 50-200 μg/g weight of thecomposition.
 4. The method of treating rhinitis according to claim 1,wherein the concentration of the CNP is 50-100 μg/g weight of thecomposition.
 5. The method of treating rhinitis according to claim 1,wherein the rhinitis is infectious rhinitis, hypersensitivenon-infectious rhinitis, irritant rhinitis, atrophic rhinitis, orspecific granulomatous rhinitis.
 6. The method of treating rhinitisaccording to claim 5, wherein the infectious rhinitis is acute rhinitisor chronic rhinitis.
 7. The method of treating rhinitis according toclaim 5, wherein the hypersensitive non-infectious rhinitis iscombined-type rhinitis (hypersensitive nose), rhinorrhea-type rhinitis,congestive-type rhinitis, or dry-type rhinitis.
 8. The method oftreating rhinitis according to claim 7, wherein the combined-typerhinitis (hypersensitive nose) is allergic rhinitis.
 9. The method oftreating rhinitis according to claim 8, wherein the allergic rhinitis isallergic rhinitis against at least one allergen selected from the groupconsisting of house dust, mite, cedar, orchard grass, ragweed, and cathair.
 10. The method of treating rhinitis according to claim 5, whereinthe irritant rhinitis is physical irritant-induced rhinitis, chemicalirritant-induced rhinitis or radiation-induced rhinitis.
 11. The methodof treating rhinitis according to claim 1, wherein the rhinitis isatrophic rhinitis or specific granulomatous rhinitis.
 12. The method oftreating rhinitis according to claim 1, wherein the rhinitis ismixed-type rhinitis, sneezing/rhinorrhea-type rhinitis, ornasal-occlusion-type rhinitis.
 13. The method of treating rhinitisaccording to claim 1, wherein the composition is selected from anointment preparation, a gel preparation, a cream preparation, a lotionpreparation, a liquid preparation, a powder preparation or a spraypreparation.
 14. The method of treating rhinitis according to claim 13,wherein the composition is selected from a gel preparation, a liquidpreparation or a spray preparation.
 15. The method of treating rhinitisaccording to claim 1, wherein the rhinitis is rhinitis in a subjectsuffering from atopic dermatitis.
 16. The method of treating rhinitisaccording to claim 1, wherein the rhinitis is rhinitis with treatmentresistance to steroids.
 17. The method of treating rhinitis according toclaim 1, wherein the rhinitis is rhinitis in a subject having adifficulty in withdrawal from steroids.
 18. The method of treatingrhinitis according to claim 1, wherein the rhinitis is rhinitis withtreatment resistance to antihistamine drugs.